Immunotherapeutic Potential of T Memory Stem Cells

Abstract

Memory T cells include T memory stem cells (T_SCM) and central memory T cells (T_CM). Compared with effector memory T cells (T_EM) and effector T cells (T_EFF), they have better durability and anti-tumor immunity. Recent studies have shown that although T_SCM has excellent self-renewal ability and versatility, if it is often exposed to antigens and inflammatory signals, T_SCM will behave as a variety of inhibitory receptors such as PD-1, TIM-3 and LAG-3 expression, and metabolic changes from oxidative phosphorylation to glycolysis. These changes can lead to the exhaustion of T cells. Cumulative evidence in animal experiments shows that it is the least differentiated cell in the memory T lymphocyte system and is a central participant in many physiological and pathological processes in humans. It has a good clinical application prospect, so it is more and more important to study the factors affecting the formation of T_SCM. This article summarizes and prospects the phenotypic and functional characteristics of T_SCM, the regulation mechanism of formation, and its application in treatment of clinical diseases.

Introduction

Immunotherapy has become one of the most promising strategies in cancer treatment, and has shown good efficacy in clinical trials (1). In particular, chimeric antigen receptor-engineered T cells (CAR-T) can specifically and effectively kill tumor cells, bringing new hopes for the treatment of patients with malignant tumors (2–7). However, whether it is traditional immune cell therapy or new CAR-T cells and T-cell receptor T cells (TCR-T) therapy, all are based on terminally differentiated effector T (T_TE) cells, making it difficult to exert long-lasting anti-tumor effects in the body (8). Adoptive T cell therapy (ACT) is the in vitro expansion and reinfusion of tumor-reactive T cells, and is a potential treatment method for the treatment of advanced cancer (9–14). In infections and cancers, T lymphocytes expand and differentiate into effector cells and memory cells that clear pathogens. These cells can survive for a long time and ensure that they have a protective effect against pathogens when they are re-attacked by antigens (15). Human T lymphocytes are generally divided into naive T cell (T_N), central memory T cell (T_CM), effector memory T cell (T_EM) and effector T cell (T_EFF). In 2005, in the study of graft versus host disease (GVHD) in mice, a group of special memory T cell subsets with super proliferation and differentiation ability was observed for the first time. It produces persistent graft-versus-host disease, which the researchers named “stem like memory T cells” (T_SCM) (16). Studies have shown that adoptively infused young T cells can self-renew and differentiate in mice, having the ability to survive for a long time, and exhibit significantly better anti-tumor capabilities than T_TE cells. The progressive differentiation of T lymphocytes leads to a gradual loss of function and therapeutic potential. These studies suggest that poorly differentiated immune cells may have more application potential in clinical treatment (17–21).

T_SCM cells have great potential in overcoming the limitations of current T cell-based immunotherapy (22–24). In mouse tumor models and human hematopoietic stem cell transplantation (HSCT) patients, T_SCM cells have higher antitumor activity and survival rate. However, the proportion of T_SCM cells in peripheral blood is low, which limits its application in immunotherapy. In this review, we summarize the latest findings, and discuss in depth the phenotype, function, differentiation mechanism and clinical application of memory T cells. It is hoped that using the therapeutic potential of T_SCM cells for adoptive immunotherapy provides new ideas. The conceptual work and key discoveries that formed this field of investigation are shown in Figure 1 (25–38), which mainly summarizes the main discoveries in the process of T_SCM cell research in recent years and the new research on the occurrence and development of diseases, some of which are introduced in articles.

Figure 1

Phenotypic and Functional Characteristics of Memory T Cells

T_SCM is a T cell subset with self-renewal ability and pluripotency potential. This group of memory T cells can play the role of acquired immune function in the process of the body’s fight against viruses or tumors (36, 39). T cell populations are classified by some surface markers, and distinguished according to their functions and sources, and the production of their effector cytokines. Memory T cells can be divided into T_CM and T_EM. T_EM cells and T_CM cells circulate in the blood and target the secondary lymphoid tissues. The degree of differentiation of T_CM cells is lower than that of T_EM and effector cells, and its telomeres are found to be longer, and the expression of perforin, granzyme and other effector molecules is lower (40). In addition, the T_SCM pool should be limited to lymph nodes and secondary lymphoid organs, which are T cells that have antigen experience. The current research results also show that T_CM has the function of T memory stem cells. T_CM has stronger immune replacement ability and stronger survival ability in vivo than T_EM cells. T_SCM is developed from naive T cells in a resting state. It is a group of cells between T_N and T_CM. It also has the characteristics of T_N cells and memory T cells (T_M), and then differentiates into T_CM and T_EM. Good et al. (41) used single-cell mass cytometry to track the proliferation history of T cells. By analyzing the changes in phenotype and protein expression of T cells at different times and in different division states, it assisted in confirming the T cell differentiation theory: T_N → T_SCM → T_CM → T_EM. It is worth noting that only naive T cells and T_SCM cells can reconstruct the heterogeneity of the entire memory T cell subset. At present, malignant tumors are one of the important diseases threatening human health, and there is no effective method to treat them. Due to their own characteristics, T_SCM cells have shown their strong potential for tumor therapy.

According to the different expressions of cell surface chemokine receptor (CCR7) and lymph node homing molecules (CD62L), memory T cells are divided into T_CM and T_EM. T_CM highly expresses CCR7 and CD62L, homing to secondary lymphoid organs, but low expression in T_EM, which preferentially transports to peripheral tissues and mediates rapid effector functions. T_SCM cells express naive cell phenotypes (CD45RA, CD62L, CCR7, CD95, CD27, CD122), and are characterized by rapid response to antigens, expression of a variety of effector molecules, and generation of memory effector cells. CD45RA⁺ is closely related to its memory ability. Naive cells express two molecules CD27 and CD45RA at the same time. Memory and effector cells only express CD27 or CD45RA respectively. T_SCM cells highly express IL-2, IFN-γ, TNF-α, Bcl- 2. IL-7 and other molecules related to early differentiation of T cells, low expression of CD57 and other molecules related to T cell senescence, showing stronger degranulation ability and the ability to produce inflammatory cytokines. Recent studies have found that by detecting the expression of CD122 or CXCR3 in healthy people by flow cytometry, the T_SCM CD122^hi-expressing subset demonstrate greater proliferation, greater multipotency and enhanced polyfunctionality with higher frequencies of triple positive (TNF-α, IL-2, IFN-γ) cytokine-producing cells upon exposure to recall antigen. The cell proliferation and multifunctional cytokine production of the T_SCM CXCR3^lo population are also significantly increased (42). Loss of CXCR3 promotes stem-like memory precursor differentiation (43). According to these surface markers, T_SCM cells can be accurately distinguished. T_SCM cells represent a subset of minimally differentiated T cells, which are characterized by phenotypic and functional characteristics that connect naive and conventional memory cells.

The above mainly describes the surface markers of human T cell subsets. In addition to the specific T cell receptor (TCR), both human and murine T_SCM express common markers of memory T cells (mouse CD62L, human CCR7, human CD45RO), and anti-apoptotic marker molecules (Bcl- 2), the cytokine receptor markers related to survival and proliferation CD122 (co-receptor of IL-2, IL-7 and IL-15) and CD127 (IL-7 receptor), stem cell marker (Sca-1). Human and murine T cell subsets are defined by different phenotypes (16, 27) (Table 1).

Development of T_SCM Cells

Manipulation to Produce T_SCM Cells in (Ex) Vivo

The relative scarcity of circulating T_SCM cells limits their use in tumor therapy, which has led to manufacturing protocols that expand this cell type in vitro. As an important participant in the function of T cells, cytokines play an important role in the maintenance and expansion of T_SCM subset. Recently reported related cytokines that can promote T_SCM expansion are shown in Figure 2. A large number of studies have shown that adding different cytokines to the immune cell culture system can make it differentiate into memory or effector T cells (44–47). γc-cytokine IL-2, as a T cell growth factor, is still the most common cytokine used to expand therapeutic T cell products for patients (29, 48–50). γc-cytokine IL-2, as a T cell growth factor, is still the most common cytokine used to expand therapeutic T cell products for patients. However, high IL-2 levels reduced the overall production of early memory T cells by reducing central memory T cells and augmenting effectors. The number of early memory T cells in the T cell subset could be increased by simply reducing the amount of IL-2 (51). In the in vitro expansion process, repeated use of IL-2 to stimulate T cells would also cause T cell depletion and reduced T cell persistence (52). IL-7 could also promote the proliferation of T_SCM cells by down-regulating the expression of programmed cell death protein 1 (PD-1) and Foxp3, and promoted the ability of CD4⁺ T cells to produce IFN-γ, IL-2, TNF-α and granzyme B. The involvement of STAT5 in IL-7-induced polyfunctionality, this the polyfunctional phenotype driven by IL-7 is associated with increased histone acetylation effector gene promoters and reveals previously unknown characteristics of IL-7 (53–56). The current study, CAR-T cells expanded in IL-15 (CAR-T/IL-15) preserved a less-differentiated T_SCM phenotype, defined by expression of CD62L⁺CD45RA⁺CCR7⁺, as compared to cells cultured in IL-2 (CAR-T/IL-2). What’s more, CAR-T/IL-15 cells exhibited reduced expression of exhaustion markers, higher anti-apoptotic properties, and increased proliferative capacity when it was attacked by antigens (57). The combined use of IL-7 and IL-15 can preserve the T_SCM phenotype and enhance the effectiveness of CAR-T cells (11, 29, 58–61). IL-21 was critical for the long-term maintenance and functionality of CD8⁺T cells and the control of chronic lymphocytic choriomeningitis virus (LCWV) infection in mice. In the process of chronic infection, cell-autonomous IL-21 receptor (IL-21R)–dependent signaling by CD8⁺ T cells was required for sustained cell proliferation and cytokine production (62, 63). IL-21 also can promote the generation of T_SCM cells. It activates the Janus kinase signal transducer and activator of transcription 3 pathway by upregulating signal transducer and activator of transcription 3 phosphorylation and thereby promoting the expression of T-bet and suppressor of cytokine signaling 1, while decreasing the expression of eomesodermin (Eomes) and GATA binding protein 3 (64). In the absence of IL-10, IL-21 or STAT3, virus-specific CD8⁺ T cells (VSTs) maintain the terminal effect (T_E) differentiation state and couldn’t mature into self-renewing T_CM cells. The maturation of protective memory T cells and memory CD8⁺ T cell precursors was an active process that depended on the IL-10-IL-21-STAT3 signal (64, 65). Whether the formation of T_SCM depends on this pathway still needs further research, but it provides new ideas for subsequent research. Lactate dehydrogenase (LDH) inhibition combined with IL-21 could increase the formation of T_SCM cells, thereby producing more profound antitumor responses and prolonging the survival time of the host (66). In addition, a new study found that by fusion of IL-21 to anti-PD-1 antibody, IL-21 can target tumor-reactive T cells to promote T_SCM production. PD-1Ab21 therapy has shown greater antitumor effects in established tumor-bearing mice (67). At present, a large number of experiments have confirmed that these cytokines can promote the production of T_SCM and have potential antitumor effects. However, the mechanism of using cytokines, drugs and checkpoint blockade to promote the differentiation of memory T cells remains to be studied.

Figure 2

Oxidative Metabolic Pathway of T_SCM Cells

The naive T cells in the circulation are quiescent and have low metabolic requirements. They mainly use oxidative phosphorylation (OXPHOS) to produce ATP (53, 68). Generally speaking, differentiated T cells use glycolysis to proliferate, while memory T cells tend to use fatty acid oxidation (FAO)-dependent oxidative phosphorylation (OXPHOS) to produce ATP, which helps to perform long-lasting antitumor response in the tumor microenvironment (69–74). In the tumor microenvironment, tumor cells inhibit the metabolic reprogramming of T cells by competitively using glycolysis, so that the formation of memory T cells is inhibited (75, 76). It is reported that important transcription factors and cytokines, as well as MEKi and other inhibitors in the process of T cell differentiation, induce the generation of T_SCM by regulating T cell-related metabolic enzymes (77–79) (Figure 3).

Figure 3

Signals from TCR, costimulatory molecules, and growth factors lead to the activation of signaling pathways that promote transcriptional programs that are critical to effector function (80–82). In memory T cells, cellular stress, such as growth factor deprivation or a low ratio of ATP/AMP, will activate AMP-activated protein kinase (AMPK) and inhibit mTOR signaling (83). IL-15 also showed a similar function (57, 83).

Good et al. (41, 84) have proved through a large number of experiments that blocking the mTOR pathway by adding inhibitors can allow T cells to differentiate towards T_SCM-like cells, such as ITK (IL-2-inducible T-cell kinase), TWS119 and BTK (Bruton’s tyrosine kinase) inhibitors. In addition, the glycolytic function of T_SCM cells is reduced, and different inhibitors promote the in vitro generation of T_SCM-like cells with unique metabolic characteristics and retained polyfunctionality. It is worth noting that the drug-induced T_SCM cells have superior functional characteristics and self-renewing capacity after adoptive transfer. The research compound Akt inhibitor VIII inhibits AKT in vitro, which can preserve the differentiation and function of minor histocompatibility antigen (MIHA)-specific CD8⁺ T cells. Moreover, transcriptome profiling revealed that AKT-inhibited CD8⁺T cells clustered closely to naturally occurring stem cell-memory CD8⁺ T cells. Moreover, AKT-inhibited MiHA-specific CD8⁺ T cells showed increased polyfunctionality with co-secretion of IFN-γ and IL-2 upon antigen recall (79). Glycerol channel aquaporin 9 (AQP9) deficiency could impair the entry of glycerol into memory CD8⁺ T cells for fatty acid esterification and triglyceride (TAG) synthesis and storage. While IL-7 could induce expression of the AQP9 in virus-specific memory CD8⁺ T cells, but not naive cells. AQP9 is essential for their long-term survival. TAG synthase could restore the survival of lipid storage and memory T cells through ectopic expression, and it was found that TAG synthase is the central component of IL-7-mediated survival of human and mouse memory CD8⁺ T cells (75). Three transcription factors, BAZ1B, PSIP1 and TSN, could regulate the level of L-arginine and promoted the survival of T cells. Activated T cells transform from glycolysis to oxidative phosphorylation, which promotes the production of T_SCM with higher survival ability and has antitumor activity in mouse models (85). Recent new studies have found that T_SCM induced by Meki/2 inhibition (Meki) has a natural phenotype, self-renewal ability, and enhanced pluripotency and proliferation. It is also achieved by regulating metabolism without affecting T cell receptor-mediated activation. DNA methylation analysis showed that Meki-induced T_SCM cells exhibited plasticity and loci-specific profiles, similar to those of T_SCM truly isolated from healthy donors, and had similar characteristics to naive and T_CM cells. Meki treatment of tumor-bearing mice also showed strong immune-mediated antitumor effects (86). These studies indicate that the regulation of glycolysis and metabolism is the key factor in inducing the formation of T_SCM. Therefore, targeted metabolic checkpoints can make T cells differentiate into memory and provide more young T cells for immunotherapy (74, 81, 82, 86).

The Molecules of Exhausted T Cells

T cell exhaustion is a phenomenon widely observed in humans. T_SCM or CAR-modified T_SCM expresses high levels of PD-1, TIM-3 or CTLA-4 after infiltrating the tumor, indicating that they have become exhausted T cells. Mostly due to T cell exhaustion and dysfunction by continuous TCR and cytokine stimulation. In addition, the effect of immune checkpoint inhibitors is very dependent on endogenous T cell function. However, they cannot reverse the exhaustion of T cells in cells that have undergone epigenetic changes. Therefore, this limits the long-term efficacy and wide application of cancer immunotherapy. Therefore, an in-depth understanding of the mechanism of T cell exhaustion is necessary for the study of T_SCM and its better clinical application. The term “ exhausted T cells” was originally derived from a mouse model of LCMV. It is now widely used to define the dysfunction state of T cells under chronic infection or tumor-induced long-term high antigen load stimulation (87). Enhanced and sustained T cell receptor stimulation is a key driver of T cell exhaustion. In recent years, the definition and identification of exhausted T cells have been divided from phenotype to transcriptional and epigenetic levels (88–90). Exhausted T cells are characterized by increased expression levels of inhibitory receptors such as PD-1, LAG3, 2B4, TIM-3 and CD28, and the gradual loss of effector functions, including impaired ability to secrete IFN-γ and tumor necrosis factor (91–95). PD-1 is mainly expressed on the surface of activated T cells and can inhibit T cell activation and proliferation. It is an important immunosuppressive molecule that plays an important role in suppressing immune responses and promoting self-tolerance (96–98). Programmed cell death ligand 1 (PD-L1) is a transmembrane protein, which is mainly expressed on the surface of antigen-presenting cells (APCs) such as dendritic cells (DCs), and can also be expressed on the surface of cancer cells and tumor infiltrating lymphocytes (TIL) (99–102). TOX is a nuclear DNA binding protein. TOX plays an important role in the development of thymus CD4⁺ T cells, NK cells and intrinsic lymphocytes, and is critical in the differentiation of tumor-specific T cells. Recent studies have described the important role of TOX in the differentiation of exhaustive CD8⁺ T cells and its molecular mechanism. It is unanimously found that the high expression of TOX is related to the high expression of a variety of inhibitory receptors (PD-1, TIM-3, TIGIT, CTLA-4, etc.) and the low expression of TCF1 (103). So inhibiting TOX expression may hinder the exhaustion of T cells (104–109). Many laboratories have identified a kind of exhausted T cell precursors (TPEX), which highly express molecules related to memory T cells, such as TCF1. TCF1 is a transcription factor and histone deacetylase (HDAC), which is related to the formation of T cell memory. Through single-cell RNA sequencing (scRNA-seq) and lineage tracing, the TCF1⁺Ly108⁺PD-1⁺CD8⁺ T cell population was identified. It was found that PD-1 stabilized the TCF1⁺TeX precursor cell pool and confirmed that PD-1 was this early stage protector of the TCF1 population (91, 110). Exhaustion first appeared in TCF1⁺ precursor T cells and then spread to the antigen-specific T cell pool. These findings will be important in the future to further investigate the developmental relationships in the later stages of exhaustion (111, 112).

At present, the specific mechanism of T cell exhaustion has not been fully elucidated. T cell exhaustion may be a parallel process with T cell differentiation. T cells at any stage of differentiation can be induced into exhausted T cells, which involves changes in different phenotypes and molecules. Excessive stimulation of precursor cells may be the origin of T cell failure. Under chronic infection or long-term tumor antigen stimulation, memory T cells and exhausted T cell precursors show different differentiation characteristics. Whether there is a link between the differentiation between these two subgroups should be a priority research area in the future. The possible potential developmental trajectories of exhausted T cells are shown in Figure 4.

Figure 4

At present, drugs for T cell exhaustion are still in the laboratory research or clinical trial stage. By reducing T cell exhaustion to promote the self-renewal ability and polyfunctionality of T_SCM cells (Table 2). Therefore, we do not know how to regulate the exhaustion process of T cells and reverse the exhausted state. Is it feasible to reach a certain effector state, and will there be side effects? Whether T_SCM can be designed to be exhaustion resistant? In general, the molecular mechanism of T_SCM cell formation is very complicated, and we describe them as clearly as possible in the review. More and more evidence supports the therapeutic potential of targeting exhausted T cells (115–118). We have already begun to understand the molecular mechanism of T cell exhaustion and early memory formation. Transforming exhausted T cells into rejuvenated T_SCM cells is the goal of our research.

Clinical Application

The Antitumor Effect of T_SCM

T_SCM cells are the least differentiated cells located at the top of the memory T lymphocyte hierarchy system. Compared with other T cells, they have stronger self-renewal ability and anti-tumor ability (84, 119, 120). As early as in previous studies, it has been found that T_SCM is considered a key determinant of immune memory and is involved in diversification of immune memory after allogeneic HSCT (32, 33). Play an important role in adult T-cell leukemia (34). With the FDA approval of CAR-T cell therapy for hematological malignancies, ACT has become a hot spot of continuous attention (63, 121–128). The clinical application of T_SCM cells is hindered because they are relatively rare in the circulation. According to reports, the CAR-T cell-modified T_SCM was cocultured with IL-2, IL-7 or IL-15 and then injected intravenously into tumor-bearing mice. It was found that the CAR-T/IL-15 group have the best anti-tumor effect (57). Guan et al. (129) prepared allogeneic antigen-specific CD8⁺ T_SCM. It showed a proliferation history and rapidly differentiated into effector cells upon the E007 [the EB virus (EBV) transformed B lymphoblastoid cell lines (LCLs)] re-stimulation. Importantly, the prepared T_SCM cells could survive for a long time and reconstituted other T cell subsets in vivo, and could effectively eliminate E007 cells after being transferred to LCL burden mice. KUN et al. (120) presented a novel tumor therapeutic modality of the cryo-thermal therapy. After 90 days of cryo-thermal therapy, it can enhance the cytolytic function of CD8⁺ T cells, induce CD8⁺ T cells to differentiate into T_SCM, and CD4⁺ T cells to differentiate into dominant CD4^- CTL, Th1 and TFH subets. Cryo-thermal therapy not only inhibits lung metastasis, but also promotes the regression of implanted melanoma and prolongs survival time (35, 130, 131). It was found that after antigen chimeric modification of T_SCM, CD19-specific CAR T cell adoptive transfer has a significant antitumor effect on leukemia and lymphoma, and the therapeutic potential seems to be related to persistence in vivo (128, 129, 132, 133).

In SIP (an ex-vivo culture system modeled after the temporal changes of essential cytokines in an acute infection), TIL in the bone marrow of patients diagnosed with acute myeloid leukemia (AML) was treated with similar SIP, and it was found that these lymphocytes can be re-transformed into mutant CD45RA⁺ central memory T lymphocytes (T_CMRA) with similar characteristics of T_SCM. The expression of pro-inflammatory cytokines, TNF-α, IFN-γ and IL-2 increased, and T_CMRA also exhibited cytotoxicity against autologous AML blast cells (134). In addition, similar effects have been shown in the treatment of Hodgkin’s lymphoma. It showed a survival advantage, had higher tumor invasion and enhanced antitumor effect (133). Tumor immunotherapy is a promising treatment method. Transfect antigen-specific TCR gene or CAR vector to T_SCM to obtain CAR-T cells with poor differentiation and greater proliferation ability (135–139). A clinical trial study found that the genetically modified T_SCM can survive in the body for up to 12 years and has good safety and function (140). Recent studies have found that through integration site analysis, it is possible to study the fate of different types of CAR-T cells in patients, and it has been observed that T_SCM plays a central role in the early anti-leukemia response and late immune surveillance (38). This shows that this small portion of T cells is critical to the long-term success of CAR-T cell therapy. This new insight may help us improve CAR-T cell therapy and find out which patients are at higher risk of recurrence, and may benefit from stem cell transplantation after CAR-T cell therapy.

To date, CAR-T cells have achieved remarkable results in the treatment of hematological malignancies. However, despite extensive research, CAR-T cells have not been so successful in the treatment of solid tumors (141). Therefore, how to increase the trafficking and extravasation of T cells to the tumor sites and encourage the proliferation of T cells in the tumor is a problem that needs to be solved urgently. T_SCM have been shown to eradicate large tumors even when limited numbers of cells were transferred (28). Studies have found that chimeric T cells with multiple antigens may be a new direction for the treatment of solid tumors (71, 141, 142). At present, there are relatively few reports on the treatment of solid tumors with CAR-T-modified T_SCM, so it is more challenging for CAR-T-modified T_SCM to target solid tumors. The future should be a priority research area. In summary, memory T cell subsets have good clinical application prospects in clinical antitumor immunotherapy, and can provide personalized treatment plans for improving the prognosis of patients (134, 143). In short, these studies provide a strong scientific basis and practical methods for the rapid advancement of T_SCM cells in clinical trials of human adoptive immunotherapy.

The Importance of T_SCM in HIV-1 Immunotherapy and Vaccine Research

T_SCM cells play a key role in the pathogenesis of human immunodeficiency virus (HIV) infection (30, 144–146). The exhaustion of these cells will lead to the deterioration of the immune system and the development of AIDS. HIV-1 is an important part of the virus reservoirs. During HIV-1 infection, CD4⁺ T_SCM cells are confirmed to be the longest-lived HIV-1. Virus storage is one of the factors that cause persistent HIV-1 infection (147, 148). Therefore, CD4⁺ T_SCM cells can be used as a new target to clear the HIV-1 virus reservoir. The virus-latent cells are mainly concentrated in CD4⁺ T_SCM. CD4⁺ T_SCM expresses lower levels of CCR5, but can still support the production and latent infection of R5-tropic HIV-1 (149, 150). In addition, CD4⁺ T_SCM is highly permissible for VSV-G-HIV-1 virus infection in vitro, and expresses relatively low levels of intracellular viral restriction factors, such as SAMHD1, Trim5alpha, and APOBEC3G. Moreover, these restriction factors can prevent HIV-1 from replicating in myeloid and dendritic cells (151–153). It was found that the CD4⁺ T_SCM of untreated HIV-1 infected persons contained high levels of HIV-1 RNA, which all indicated the sensitivity of CD4⁺ T_SCM cells to HIV-1. The study also found that in patients undergoing antiretroviral therapy (ART), CD4⁺ T_SCM cells also have viral DNA that can be activated. Moreover, among the subsets of CD4⁺ T memory cells, the number of HIV-1 DNA in T_SCM cells is the highest. During HIV infection, T cells play an important role in controlling virus replication. In patients receiving inhibitory antiretroviral therapy, CD8⁺ T_SCM with stem cell characteristics was found to be more abundant than untreated patients (154). In addition, prolonging the treatment time can increase the ratio of CD8⁺ T_SCM, and preferentially secrete IL-2 under viral stimulation, indicating that CD8⁺ T_SCM is an important part of the cellular immune response to HIV-1. Able to maintain long-term, non-antigen-dependent cellular immune memory for HIV-1, which plays a key role in HIV control, but it seems unable to survive and proliferate during untreated infections (149). It is worth noting that HIV-1 specific CD8⁺ T_SCM cells may not directly participate in the antiviral process, but play a role by secreting IL-2 to maintain their own proliferation and differentiation (155–157). Recent studies have found that vaccination of the subtype C prophylactic HIV-1 vaccine candidate can induce more T_SCM and antiviral. Compared with MVA alone and placebo, it induces more peripheral CD8⁺ T_SCM cells and a higher level of CD8⁺ T cell-mediated inhibition of the replication of different HIV-1 branches can respond to acute HIV infection or effectively control the chronic replication of HIV (152). Recently, a cross-sectional study of 20 cases of HIV-infected patients on treatment alone and 20 cases of ART has revealed a new subset of CD4⁺ T cells: follicular regulatory T cells (TFR). The TFR of HIV⁺ patients had anti-apoptotic properties, high proliferation rate and T_SCM-like properties, which leaded to the expansion of TFR, which in turn leaded to the dysfunction of TFH. Therefore, TFR cells may also become a new and potential therapeutic target for the treatment of HIV infection (158). How to target T_SCM therapy to provide new ideas for the development of new strategies for HIV-1 vaccines and immunotherapy still needs to continue to be explored and studied.

T_SCM and Autoimmune Diseases

T_SCM cells provide long-term protective immunity for anti-tumor immunity, which is probably based on reactivity to self-antigens. Therefore, as a by-product of antitumor, T_SCM-mediated autoimmunity is inevitable (18, 159). Recent related studies have reported that T_SCM cells are associated with a variety of autoimmune diseases. Systemic lupus erythematosus (SLE) is a chronic connective tissue disease involving multiple organs that occurs in young women. Compared with healthy controls, the percentage of CD4⁺ and CD8⁺ T_SCM cells in SLE patients increased significantly. Differentiated TFH cells increase the antibodies produced by their own B cells. T_SCM cells play a role in the pathogenesis of SLE by maintaining TFH cells (132). Moreover, compared with healthy controls, the CD4⁺ T_SCM of rheumatoid arthritis (RA) patients increased significantly (160). In the presence of IL-6, TCRs are easily activated to produce inflammatory cytokines. T_SCM cells may be a continuous source of the pathogenicity of RA (161). In patients with immune thrombocytopenia (ITP), the ratio of CD4⁺ and CD8⁺ T cells in the peripheral blood is unbalanced. The percentage of CD8⁺ T_SCM in peripheral blood of ITP patients was significantly reduced after glucocorticoid treatment, indicating that the imbalance of the ratio of CD8⁺ T_SCM may be involved in the occurrence and development of ITP (162). In addition, the frequency of acquired aplastic anemia (AA) CD8⁺ T_SCM after immunosuppressive treatment was significantly higher than that of healthy controls. The frequency of CD8⁺ T_SCM is also elevated in patients with autoimmune uveitis or sickle cell disease (130). B-cell-specific CD8⁺ T_SCM cells with high expression of glucose transporter 1 (GLUT1) can be detected in T1D patients. WZB117, a selective inhibitor of Gult-1, effectively inhibits T_SCM cells in type 1 diabetes (T1D) patients by inhibiting glucose metabolism (53). Long-term autoreactive or abnormally activated T_SCM cells may induce self-renewing inflammatory cell responses. Studies have found that rapamycin (mTORC1 inhibitor) is outstanding in the treatment of autoimmune diseases (163). The above studies indicate that T_SCM may be a potential therapeutic target for these autoimmune diseases. The possible role of T_SCM cells in other diseases with severe cellular immune response, such as autoimmune hepatitis, thyroiditis, and certain types of glomerulonephritis, is currently unclear, but represents a priority research area in the future.

Conclusion

T_SCM is a long-lived memory cell with self-renewal ability and multi-differentiation potential. Different subsets of memory T cells can be identified based on their surface markers, gene expression profiles, and metabolic methods. At the same time, clinical-grade memory T cells can be obtained through in vitro induction and culture for cell transfer. The formation of memory T cells in the body has been confirmed in pre-clinical trials. The genetically modified T_SCM can survive in the body for up to 12 years and has good safety and function (140, 164). Convincing evidence in mice and humans shows that T_SCM cells are an important tool for adoptive immunity in tumor immunotherapy (143, 162). On the contrary, it is precisely because of their powerful immune reconstruction ability that they play a double-edged role in human diseases, and they are also potential therapeutic targets for autoimmune diseases and HIV (Figure 5). However, there are still many problems that need to be solved, elucidating the molecular mechanism of maintaining the phenotype of T_SCM cells and the influence of epigenetic modification, how to obtain a sufficient number of clinical grade T_SCM for induction culture. The infused T_SCM cells are easily affected by the immune microenvironment and are difficult to exert antitumor effects, and how the T_SCM cells target the tumor site to kill tumor cells is a problem worthy of attention at present. CAR-modified T_SCM cells, although there is good preclinical evidence that they have anti-tumor activity, when they are intravenously infused into solid tumor patients, they still lack persistence and efficacy (71, 133, 142). At the same time, it is worth noting that a single treatment method cannot effectively eliminate tumor cells. Immune cell therapy should be combined with PD-1 monoclonal antibody, CTLA-4 monoclonal antibody or radiotherapy, chemotherapy and other treatment methods, so that patients can get better efficacy (165). T_SCM has long existed in the HIV-1 virus reservoir, so future research is necessary to determine whether the low virus accumulation in T_SCM cells represents a significant feature of HIV-1 infection. More effort is needed to clarify the changes between the different states of T_SCM cells in health and disease. Although significant progress has been made in tumor therapy, there is still a gap in our understanding of the role of T_SCM cells in autoimmunity and viral infections.

Figure 5

Funding

This work was funded by the Guangxi Science and Technology Research Base and Talent-specific Project (AD18126021); National Science and Technology Major Project for New Drug Innovation (2018ZX09733001-004-002); National Natural Science Foundation of China (NSFC) project (No. 81872491); Key Laboratory of the Ministry of Education Project for Early Prevention and Treatment of Regional High-risk Tumors (GKE2018-03, GKE2019-09, GKE-ZZ202007).

Publisher’s Note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

References

• 1

  MillerJDvan der MostRGAkondyRSGlidewellJTAlbottSMasopustDet al. Human Effector and Memory CD8+ T Cell Responses to Smallpox and Yellow Fever Vaccines. Immunity (2008) 28(5):710–22. doi: 10.1016/j.immuni.2008.02.020

  • CrossRef
  • Google Scholar

• 2

  FigueroaJAReidyAMirandolaLTrotterKSuvoravaNFigueroaAet al. Chimeric Antigen Receptor Engineering: A Right Step in the Evolution of Adoptive Cellular Immunotherapy. Int Rev Immunol (2015) 34(2):154–87. doi: 10.3109/08830185.2015.1018419

  • CrossRef
  • Google Scholar

• 3

  KhouriRSilva-SantosGDierckxTMenezesSMDecanineDTheysKet al. A Genetic IFN/STAT1/FAS Axis Determines CD4 T Stem Cell Memory Levels and Apoptosis in Healthy Controls and Adult T-Cell Leukemia Patients. Oncoimmunology (2018) 7(5):e1426423. doi: 10.1080/2162402X.2018.1426423

  • CrossRef
  • Google Scholar

• 4

  LiXChenW. Mechanisms of Failure of Chimeric Antigen Receptor T-Cell Therapy. Curr Opin Hematol (2019) 26(6):427–33. doi: 10.1097/MOH.0000000000000548

  • CrossRef
  • Google Scholar

• 5

  MartinezMMoonEK. CAR T Cells for Solid Tumors: New Strategies for Finding, Infiltrating, and Surviving in the Tumor Microenvironment. Front Immunol (2019) 10:128. doi: 10.3389/fimmu.2019.00128

  • CrossRef
  • Google Scholar

• 6

  ZhaoJSongYLiuD. Clinical Trials of Dual-Target CAR T Cells, Donor-Derived CAR T Cells, and Universal CAR T Cells for Acute Lymphoid Leukemia. J Hematol Oncol (2019) 12(1):17. doi: 10.1186/s13045-019-0705-x

  • CrossRef
  • Google Scholar

• 7

  XuLYaoDTanJHeZYuZChenJet al. Memory T Cells Skew Toward Terminal Differentiation in the CD8+ T Cell Population in Patients With Acute Myeloid Leukemia. J Hematol Oncol (2018) 11(1):93. doi: 10.1186/s13045-018-0636-y

  • CrossRef
  • Google Scholar

• 8

  ThommenDSSchumacherTN. T Cell Dysfunction in Cancer. Cancer Cell (2018) 33(4):547–62. doi: 10.1016/j.ccell.2018.03.012

  • CrossRef
  • Google Scholar

• 9

  ShengSYGuYChuan GangLTangYYYong ZouJQing ZhangYet al. The Characteristics of Naive-Like T Cells in Tumor-Infiltrating Lymphocytes From Human Lung Cancer. J Immunother (2017) 40(1):1–10. doi: 10.1097/CJI.0000000000000147

  • CrossRef
  • Google Scholar

• 10

  ZhengCZhengLYooJKGuoHZhangYGuoXet al. Landscape of Infiltrating T Cells in Liver Cancer Revealed by Single-Cell Sequencing. Cell (2017) 169(7):1342–56.e1316. doi: 10.1016/j.cell.2017.05.035

  • CrossRef
  • Google Scholar

• 11

  ArcangeliSFalconeLCamisaBDe GirardiFBiondiMGiglioFet al. Next-Generation Manufacturing Protocols Enriching TSCM CAR T Cells Can Overcome Disease-Specific T Cell Defects in Cancer Patients. Front Immunol (2020) 11:1217. doi: 10.3389/fimmu.2020.01217

  • CrossRef
  • Google Scholar

• 12

  KrishnaSLoweryFJCopelandARBahadirogluEMukherjeeRJiaLet al. Stem-Like CD8 T Cells Mediate Response of Adoptive Cell Immunotherapy Against Human Cancer. Science (2020) 370(6522):1328–34. doi: 10.1126/science.abb9847

  • CrossRef
  • Google Scholar

• 13

  VahidiYBagheriMGhaderiAFaghihZ. CD8-Positive Memory T Cells in Tumor-Draining Lymph Nodes of Patients With Breast Cancer. BMC Cancer (2020) 20(1):257. doi: 10.1186/s12885-020-6714-x

  • CrossRef
  • Google Scholar

• 14

  WuTDMadireddiSde AlmeidaPEBanchereauRChenYJChitreASet al. Peripheral T Cell Expansion Predicts Tumour Infiltration and Clinical Response. Nature (2020) 579(7798):274–8. doi: 10.1038/s41586-020-2056-8

  • CrossRef
  • Google Scholar

• 15

  LiuQSunZChenL. Memory T Cells: Strategies for Optimizing Tumor Immunotherapy. Protein Cell (2020) 11(8):549–64. doi: 10.1007/s13238-020-00707-9

  • CrossRef
  • Google Scholar

• 16

  ZhangYJoeGHexnerEZhuJEmersonSG. Host-Reactive CD8+ Memory Stem Cells in Graft-Versus-Host Disease. Nat Med (2005) 11(12):1299–305. doi: 10.1038/nm1326

  • CrossRef
  • Google Scholar

• 17

  QianCWYCaiHLaroyeCDe Carvalho BittencourtMClementLet al. Adenovirus-Specific T-Cell Subsets in Human Peripheral Blood and After IFN-γ Immunomagnetic Selection. J Immunother (Qian 2016) 39(1):27–35. doi: 10.1097/CJI.0000000000000105

  • CrossRef
  • Google Scholar

• 18

  GaoSLiangXWangHBaoBZhangKZhuYet al. Stem Cell-Like Memory T Cells: A Perspective From the Dark Side. Cell Immunol (2021) 361:104273. doi: 10.1016/j.cellimm.2020.104273

  • CrossRef
  • Google Scholar

• 19

  XuLZhangYLuoGLiY. The Roles of Stem Cell Memory T Cells in Hematological Malignancies. J Hematol Oncol (2015) 8:113. doi: 10.1186/s13045-015-0214-5

  • CrossRef
  • Google Scholar

• 20

  LugliEGattinoniLRobertoAMavilioDPriceDARestifoNPet al. Identification, Isolation and In Vitro Expansion of Human and Nonhuman Primate T Stem Cell Memory Cells. Nat Protoc (2013) 8(1):33–42. doi: 10.1038/nprot.2012.143

  • CrossRef
  • Google Scholar

• 21

  AndoMItoMSriratTKondoTYoshimuraA. Memory T Cell, Exhaustion, and Tumor Immunity. Immunol Med (2020) 43(1):1–9. doi: 10.1080/25785826.2019.1698261

  • CrossRef
  • Google Scholar

• 22

  MorrotA. Human Stem Memory T Cells (TSCM) as Critical Players in the Long-Term Persistence of Immune Responses. Ann Transl Med (2017) 5(5):120. doi: 10.21037/atm.2017.02.28

  • CrossRef
  • Google Scholar

• 23

  GuoXZhangYZhengLZhengCSongJZhangQet al. Global Characterization of T Cells in Non-Small-Cell Lung Cancer by Single-Cell Sequencing. Nat Med (2018) 24(7):978–85. doi: 10.1038/s41591-018-0045-3

  • CrossRef
  • Google Scholar

• 24

  CheblouneYMoussaMArrode-BrusésGRonfortCBoseDGagnonJet al. A Single Lentivector DNA Based Immunization Contains a Late Heterologous SIVmac251 Mucosal Challenge Infection. Vaccine (2020) 38(21):3729–39. doi: 10.1016/j.vaccine.2020.03.053

  • CrossRef
  • Google Scholar

• 25

  FearonDTMandersPWagnerSD. Arrested Differentiation, The Self-Renewing Memory Lymphocyte, and Vaccination. Science (2001) 293(5528):248–50. doi: 10.1126/science.1062589

  • CrossRef
  • Google Scholar

• 26

  LuckeyCJBDGoldrathAWWeissmanILBenoistCMathisD. Memory T and Memory B Cells Share a Transcriptional Program of Self-Renewal With Long-Term Hematopoietic Stem Cells. Proc Natl Acad Sci USA (2006) 103(9):3304–9. doi: 10.1073/pnas.0511137103

  • CrossRef
  • Google Scholar

• 27

  GattinoniLZhongXSPalmerDCJiYHinrichsCSYuZet al. Wnt Signaling Arrests Effector T Cell Differentiation and Generates CD8+ Memory Stem Cells. Nat Med (2009) 15(7):808–13. doi: 10.1038/nm.1982

  • CrossRef
  • Google Scholar

• 28

  GattinoniLLugliEJiYPosZPaulosCMQuigleyMFet al. A Human Memory T Cell Subset With Stem Cell-Like Properties. Nat Med (2011) 17(10):1290–7. doi: 10.1038/nm.2446

  • CrossRef
  • Google Scholar

• 29

  CieriNCamisaBCocchiarellaFForcatoMOliveiraGProvasiEet al. IL-7 and IL-15 Instruct the Generation of Human Memory Stem T Cells From Naive Precursors. Blood (2013) 121(4):573–84. doi: 10.1182/blood-2012-05-431718

  • CrossRef
  • Google Scholar

• 30

  BuzonMJSunHLiCShawASeissKOuyangZet al. HIV-1 Persistence in CD4+ T Cells With Stem Cell-Like Properties. Nat Med (2014) 20(2):139–42. doi: 10.1038/nm.3445

  • CrossRef
  • Google Scholar

• 31

  GraefPBuchholzVRStembergerCFlossdorfMHenkelLSchiemannMet al. Serial Transfer of Single-Cell-Derived Immunocompetence Reveals Stemness of CD8(+) Central Memory T Cells. Immunity (2014) 41(1):116–26. doi: 10.1016/j.immuni.2014.05.018

  • CrossRef
  • Google Scholar

• 32

  RobertoACastagnaLZanonVBramantiSCrocchioloRMcLarenJEet al. Role of Naive-Derived T Memory Stem Cells in T-Cell Reconstitution Following Allogeneic Transplantation. Blood (2015) 125(18):2855–64. doi: 10.1182/blood-2014-11-608406

  • CrossRef
  • Google Scholar

• 33

  CieriNOliveiraGGrecoRForcatoMTaccioliCCianciottiBet al. Generation of Human Memory Stem T Cells After Haploidentical T-Replete Hematopoietic Stem Cell Transplantation. Blood (2015) 125(18):2865–74. doi: 10.1182/blood-2014-11-608539

  • CrossRef
  • Google Scholar

• 34

  NagaiYKawaharaMHishizawaMShimazuYSuginoNFujiiSet al. T Memory Stem Cells are the Hierarchical Apex of Adult T-Cell Leukemia. Blood (2015) 125(23):3527–35. doi: 10.1182/blood-2014-10-607465

  • CrossRef
  • Google Scholar

• 35

  SabatinoMHuJSommarivaMGautamSFellowesVHockerJDet al. Generation of Clinical-Grade CD19-Specific CAR-Modified CD8+ Memory Stem Cells for the Treatment of Human B-Cell Malignancies. Blood (2016) 128(4):519–28. doi: 10.1182/blood-2015-11-683847

  • CrossRef
  • Google Scholar

• 36

  NovielloMManfrediFRuggieroEPeriniTOliveiraGCortesiFet al. Bone Marrow Central Memory and Memory Stem T-Cell Exhaustion in AML Patients Relapsing After HSCT. Nat Commun (2019) 10(1):1065. doi: 10.1038/s41467-019-08871-1

  • CrossRef
  • Google Scholar

• 37

  GallettiGDe SimoneGMazzaEMCPuccioSMezzanotteCBiTMet al. Two Subsets of Stem-Like CD8(+) Memory T Cell Progenitors With Distinct Fate Commitments in Humans. Nat Immunol (2020) 21(12):1552–62. doi: 10.1038/s41590-020-0791-5

  • CrossRef
  • Google Scholar

• 38

  BiascoLIzotovaNRivatCGhorashianSRichardsonRGuvenelAet al. Clonal Expansion of T Memory Stem Cells Determines Early Anti-Leukemic Responses and Long-Term CAR T Cell Persistence in Patients. Nat Cancer (2021) 2(6):629–42. doi: 10.1038/s43018-021-00207-7

  • CrossRef
  • Google Scholar

• 39

  YanCChangJSongXYanFYuWAnYet al. Memory Stem T Cells Generated by Wnt Signaling From Blood of Human Renal Clear Cell Carcinoma Patients. Cancer Biol Med (2019) 16(1):109–24. doi: 10.20892/j.issn.2095-3941.2018.0118

  • CrossRef
  • Google Scholar

• 40

  Costa Del AmoPLahoz-BeneytezJBoelenLAhmedRMinersKLZhangYet al. Human TSCM Cell Dynamics In Vivo Are Compatible With Long-Lived Immunological Memory and Stemness. PloS Biol (2018) 16(6):e2005523. doi: 10.1371/journal.pbio.2005523

  • CrossRef
  • Google Scholar

• 41

  GoodZBorgesLVivanco GonzalezNSahafBSamusikNTibshiraniRet al. Proliferation Tracing With Single-Cell Mass Cytometry Optimizes Generation of Stem Cell Memory-Like T Cells. Nat Biotechnol (2019) 37(3):259–66. doi: 10.1038/s41587-019-0033-2

  • CrossRef
  • Google Scholar

• 42

  ZhaoYCaiCSamirJPalgenJLKeoshkerianELiHet al. Human CD8 T-Stem Cell Memory Subsets Phenotypic and Functional Characterization are Defined by Expression of CD122 or CXCR3. Eur J Immunol (2021) 51(7):1732–47. doi: 10.1002/eji.202049057

  • CrossRef
  • Google Scholar

• 43

  DuckworthBCLafouresseFWimmerVCBroomfieldBJDalitLAlexandreYOet al. Effector and Stem-Like Memory Cell Fates are Imprinted in Distinct Lymph Node Niches Directed by CXCR3 Ligands. Nat Immunol (2021) 22(4):434–48. doi: 10.1038/s41590-021-00878-5

  • CrossRef
  • Google Scholar

• 44

  SantegoetsSJAMTurksmaAWSuhoskiMMStamAGMAlbeldaSMHooijbergEet al. IL-21 Promotes the Expansion of CD27+ CD28+ Tumor Infiltrating Lymphocytes With High Cytotoxic Potential and Low Collateral Expansion of Regulatory T Cells. Transl Med (2013) 11(1):37. doi: 10.1186/1479-5876-11-37

  • CrossRef
  • Google Scholar

• 45

  BeckerTCWherryEJBooneDMurali-KrishnaKAntiaRMaAet al. Interleukin 15 Is Required for Proliferative Renewal of Virus-Specific Memory CD8 T Cells. J Exp Med (2002) 195(12):1541–8. doi: 10.1084/jem.20020369

  • CrossRef
  • Google Scholar

• 46

  YiJSDuMZajacAJ. A Vital Role for Interleukin-21 in the Control of a Chronic Viral Infection. Science (2009) 324(5934):1572–6. doi: 10.1126/science.1175194

  • CrossRef
  • Google Scholar

• 47

  HashimotoMImSJArakiKAhmedR. Cytokine-Mediated Regulation of CD8 T-Cell Responses During Acute and Chronic Viral Infection. Cold Spring Harb Perspect Biol (2019) 11(1):a028464. doi: 10.1101/cshperspect.a028464

  • CrossRef
  • Google Scholar

• 48

  HurtonLVSinghHNajjarAMSwitzerKCMiTMaitiSet al. Tethered IL-15 Augments Antitumor Activity and Promotes a Stem-Cell Memory Subset in Tumor-Specific T Cells. Proc Natl Acad Sci USA (2016) 113(48):E7788–97. doi: 10.1073/pnas.1610544113

  • CrossRef
  • Google Scholar

• 49

  MartkamchanSOnlamoonNWangSPattanapanyasatKAmmaranondP. The Effects of Anti-CD3/CD28 Coated Beads and IL-2 on Expanded T Cell for Immunotherapy. Adv Clin Exp Med (2016) 25(5):821–8. doi: 10.17219/acem/35771

  • CrossRef
  • Google Scholar

• 50

  Perdomo-CelisFMedina-MorenoSDavisHBryantJTabordaNARugelesMTet al. Characterization of CXCR5(+) CD8(+) T-Cells in Humanized NSG Mice. Immunobiology (2020) 225(2):151885. doi: 10.1016/j.imbio.2019.11.020

  • CrossRef
  • Google Scholar

• 51

  KaartinenTLuostarinenAMaliniemiPKetoJArvasMBeltHet al. Low Interleukin-2 Concentration Favors Generation of Early Memory T Cells Over Effector Phenotypes During Chimeric Antigen Receptor T-Cell Expansion. Cytotherapy (2017) 19(6):689–702. doi: 10.1016/j.jcyt.2017.03.067

  • CrossRef
  • Google Scholar

• 52

  GattinoniLKlebanoffCAPalmerDCWrzesinskiCKerstannKYuZet al. Acquisition of Full Effector Function In Vitro Paradoxically Impairs the In Vivo Antitumor Efficacy of Adoptively Transferred CD8+ T Cells. J Clin Invest (2005) 115(6):1616–26. doi: 10.1172/JCI24480

  • CrossRef
  • Google Scholar

• 53

  VignaliDCantarelliEBordignonCCanuACitroAAnnoniAet al. Detection and Characterization of CD8 + Autoreactive Memory Stem T Cells in Patients With Type 1 Diabetes. Diabetes (2018) 67(5):936–45. doi: 10.2337/db17-1390

  • CrossRef
  • Google Scholar

• 54

  AbdelsamedHAMoustakiAFanYDograPGhoneimHEZebleyCCet al. Human Memory CD8 T Cell Effector Potential Is Epigenetically Preserved During In Vivo Homeostasis. J Exp Med (2017) 214(6):1593–606. doi: 10.1084/jem.20161760

  • CrossRef
  • Google Scholar

• 55

  AdachiKKanoYNagaiTOkuyamaNSakodaYTamadaK. IL-7 and CCL19 Expression in CAR-T Cells Improves Immune Cell Infiltration and CAR-T Cell Survival in the Tumor. Nat Biotechnol (2018) 36(4):346–51. doi: 10.1038/nbt.4086

  • CrossRef
  • Google Scholar

• 56

  ZanonVLugliE. Differentiation of Diverse Progenies of Memory T Cells From Naive CD8(+) T Cell Precursors. Methods Mol Biol (2017) 1514:103–10. doi: 10.1007/978-1-4939-6548-9_8

  • CrossRef
  • Google Scholar

• 57

  AlizadehDWongRAYangXWangDPecoraroJRKuoCFet al. IL15 Enhances CAR-T Cell Antitumor Activity by Reducing Mtorc1 Activity and Preserving Their Stem Cell Memory Phenotype. Cancer Immunol Res (2019) 7(5):759–72. doi: 10.1158/2326-6066.CIR-18-0466

  • CrossRef
  • Google Scholar

• 58

  KondoTImuraYChikumaSHibinoSOmata-MiseSAndoMet al. Generation and Application of Human Induced-Stem Cell Memory T Cells for Adoptive Immunotherapy. Cancer Sci (2018) 109(7):2130–40. doi: 10.1111/cas.13648

  • CrossRef
  • Google Scholar

• 59

  HerdaSHeimannAObermayerBCiraoloEAlthoffSRussJet al. Long-Term In Vitro Expansion Ensures Increased Yield of Central Memory T Cells as Perspective for Manufacturing Challenges. Int J Cancer (2021) 148(12):3097–110. doi: 10.1002/ijc.33523

  • CrossRef
  • Google Scholar

• 60

  ManfrediFAbbatiDCianciottiBCStasiLPotenzaARuggieroEet al. Flow Cytometry Data Mining by Cytochain Identifies Determinants of Exhaustion and Stemness in TCR-Engineered T Cells. Eur J Immunol (2021) 51(8):1992–2005. doi: 10.1002/eji.202049103

  • CrossRef
  • Google Scholar

• 61

  CastellaMCaballero-BanosMOrtiz-MaldonadoVGonzalez-NavarroEASuneGAntonana-VidosolaAet al. Point-Of-Care CAR T-Cell Production (ARI-0001) Using a Closed Semi-Automatic Bioreactor: Experience From an Academic Phase I Clinical Trial. Front Immunol (2020) 11:482. doi: 10.3389/fimmu.2020.00482

  • CrossRef
  • Google Scholar

• 62

  FröhlichAKisielowJSchmitzIFreigangSShamshievATWeberJet al. IL-21R on T Cells Is Critical for Sustained Functionality and Control of Chronic Viral Infection. Science (2009) 324(5934):1576–80. doi: 10.1126/science.1172815

  • CrossRef
  • Google Scholar

• 63

  WuSZhuWPengYWangLHongYHuangLet al. The Antitumor Effects of Vaccine-Activated CD8(+) T Cells Associate With Weak TCR Signaling and Induction of Stem-Like Memory T Cells. Cancer Immunol Res (2017) 5(10):908–19. doi: 10.1158/2326-6066.CIR-17-0016

  • CrossRef
  • Google Scholar

• 64

  ChenYYFJiangYChenJWuKChenXet al. Adoptive Transfer of Interleukin-21-Stimulated Human CD8+ T Memory Stem Cells Efficiently Inhibits Tumor Growth. Immunother (2018) 41(6):274–83. doi: 10.1097/CJI.0000000000000229

  • CrossRef
  • Google Scholar

• 65

  CuiWLiuYWeinsteinJSCraftJKaechSM. An Interleukin-21-Interleukin-10-STAT3 Pathway Is Critical for Functional Maturation of Memory CD8+ T Cells. Immunity (2011) 35(5):792–805. doi: 10.1016/j.immuni.2011.09.017

  • CrossRef
  • Google Scholar

• 66

  HermansDGautamSGarcia-CanaverasJCGromerDMitraSSpolskiRet al. Lactate Dehydrogenase Inhibition Synergizes With IL-21 to Promote CD8(+) T Cell Stemness and Antitumor Immunity. Proc Natl Acad Sci USA (2020) 117(11):6047–55. doi: 10.1073/pnas.1920413117

  • CrossRef
  • Google Scholar

• 67

  LiYCongYJiaMHeQZhongHZhaoYet al. Targeting IL-21 to Tumor-Reactive T Cells Enhances Memory T Cell Responses and Anti-PD-1 Antibody Therapy. Nat Commun (2021) 12(1):951. doi: 10.1038/s41467-021-21241-0

  • CrossRef
  • Google Scholar

• 68

  PearceELWalshMCCejasPJHarmsGMShenHWangLSet al. Enhancing CD8 T-Cell Memory by Modulating Fatty Acid Metabolism. Nature (2009) 460(7251):103–7. doi: 10.1038/nature08097

  • CrossRef
  • Google Scholar

• 69

  JohnsonMOWolfMMMaddenMZAndrejevaGSugiuraAContrerasDCet al. Distinct Regulation of Th17 and Th1 Cell Differentiation by Glutaminase-Dependent Metabolism. Cell (2018) 175(7):1780–95.e1719. doi: 10.1016/j.cell.2018.10.001

  • CrossRef
  • Google Scholar

• 70

  ZhangJYZhaoYLLvYPChengPChenWDuanMet al. Modulation of CD8(+) Memory Stem T Cell Activity and Glycogen Synthase Kinase 3beta Inhibition Enhances Anti-Tumoral Immunity in Gastric Cancer. Oncoimmunology (2018) 7(4):e1412900. doi: 10.1080/2162402X.2017.1412900

  • CrossRef
  • Google Scholar

• 71

  KlampatsaADimouVAlbeldaSM. Mesothelin-Targeted CAR-T Cell Therapy for Solid Tumors. Expert Opin Biol Ther (2021) 21(4):473–86. doi: 10.1080/14712598.2021.1843628

  • CrossRef
  • Google Scholar

• 72

  SinclairLVRolfJEmslieEShiY-BTaylorPMCantrellDA. Control of Amino-Acid Transport by Antigen Receptors Coordinates the Metabolic Reprogramming Essential for T Cell Differentiation. Nat Immunol (2013) 14(5):500–8. doi: 10.1038/ni.2556

  • CrossRef
  • Google Scholar

• 73

  O'SullivanDvan der WindtGJHuangSCCurtisJDChangCHBuckMDet al. Memory CD8(+) T Cells Use Cell-Intrinsic Lipolysis to Support the Metabolic Programming Necessary for Development. Immunity (2014) 41(1):75–88. doi: 10.1016/j.immuni.2014.06.005

  • CrossRef
  • Google Scholar

• 74

  KondoTAndoMNagaiNTomisatoWSriratTLiuBet al. The NOTCH-FOXM1 Axis Plays a Key Role in Mitochondrial Biogenesis in the Induction of Human Stem Cell Memory-Like CAR-T Cells. Cancer Res (2020) 80(3):471–83. doi: 10.1158/0008-5472.CAN-19-1196

  • CrossRef
  • Google Scholar

• 75

  CuiGStaronMMGraySMHoPCAmezquitaRAWuJet al. IL-7-Induced Glycerol Transport and TAG Synthesis Promotes Memory CD8+ T Cell Longevity. Cell (2015) 161(4):750–61. doi: 10.1016/j.cell.2015.03.021

  • CrossRef
  • Google Scholar

• 76

  ChangCHPearceEL. Emerging Concepts of T Cell Metabolism as a Target of Immunotherapy. Nat Immunol (2016) 17(4):364–8. doi: 10.1038/ni.3415

  • CrossRef
  • Google Scholar

• 77

  HuZZouQSuB. Regulation of T Cell Immunity by Cellular Metabolism. Front Med (2018) 12(4):463–72. doi: 10.1007/s11684-018-0668-2

  • CrossRef
  • Google Scholar

• 78

  MaRJiTZhangHDongWChenXXuPet al. A Pck1-Directed Glycogen Metabolic Program Regulates Formation and Maintenance of Memory CD8(+) T Cells. Nat Cell Biol (2018) 20(1):21–7. doi: 10.1038/s41556-017-0002-2

  • CrossRef
  • Google Scholar

• 79

  MoussetCMHoboWJiYFredrixHDe GiorgiVAllisonRDet al. Ex Vivo AKT-Inhibition Facilitates Generation of Polyfunctional Stem Cell Memory-Like CD8(+) T Cells for Adoptive Immunotherapy. Oncoimmunology (2018) 7(10):e1488565. doi: 10.1080/2162402X.2018.1488565

  • CrossRef
  • Google Scholar

• 80

  GiulianiC. The Flavonoid Quercetin Induces AP-1 Activation in FRTL-5 Thyroid Cells. Antioxidants (Basel) (2019) 8(5):112. doi: 10.3390/antiox8050112

  • CrossRef
  • Google Scholar

• 81

  KaredHTanSWLauMCChevrierMTanCHowWet al. Immunological History Governs Human Stem Cell Memory CD4 Heterogeneity via the Wnt Signaling Pathway. Nat Commun (2020) 11(1):821. doi: 10.1038/s41467-020-14442-6

  • CrossRef
  • Google Scholar

• 82

  KolanSSLiGWikJAMalachinGGuoSKolanPet al. Cellular Metabolism Dictates T Cell Effector Function in Health and Disease. Scand J Immunol (2020) 92(5):e12956. doi: 10.1111/sji.12956

  • CrossRef
  • Google Scholar

• 83

  MaEHPoffenbergerMCWongAHJonesRG. The Role of AMPK in T Cell Metabolism and Function. Curr Opin Immunol (2017) 46:45–52. doi: 10.1016/j.coi.2017.04.004

  • CrossRef
  • Google Scholar

• 84

  ScholzGJandusCZhangLGrandclementCLopez-MejiaICSonesonCet al. Modulation of mTOR Signalling Triggers the Formation of Stem Cell-Like Memory T Cells. EBioMedicine (2016) 4:50–61. doi: 10.1016/j.ebiom.2016.01.019

  • CrossRef
  • Google Scholar

• 85

  GeigerRRieckmannJCWolfTBassoCFengYFuhrerTet al. L-Arginine Modulates T Cell Metabolism and Enhances Survival and Anti-Tumor Activity. Cell (2016) 167(3):829–42.e813. doi: 10.1016/j.cell.2016.09.031

  • CrossRef
  • Google Scholar

• 86

  VermaVJafarzadehNBoiSKunduSJiangZFanYet al. MEK Inhibition Reprograms CD8(+) T Lymphocytes Into Memory Stem Cells With Potent Antitumor Effects. Nat Immunol (2021) 22(1):53–66. doi: 10.1038/s41590-020-00818-9

  • CrossRef
  • Google Scholar

• 87

  UtzschneiderDTCharmoyMChennupatiVPousseLFerreiraDPCalderon-CopeteSet al. T Cell Factor 1-Expressing Memory-Like CD8(+) T Cells Sustain the Immune Response to Chronic Viral Infections. Immunity (2016) 45(2):415–27. doi: 10.1016/j.immuni.2016.07.021

  • CrossRef
  • Google Scholar

• 88

  WuTJiYMosemanEAXuHCManglaniMKirbyMet al. The TCF1-Bcl6 Axis Counteracts Type I Interferon to Repress Exhaustion and Maintain T Cell Stemness. Sci Immunol (2016) 1(6):eaai8593. doi: 10.1126/sciimmunol.aai8593

  • CrossRef
  • Google Scholar

• 89

  KondoTMoritaROkuzonoYNakatsukasaHSekiyaTChikumaSet al. Notch-Mediated Conversion of Activated T Cells Into Stem Cell Memory-Like T Cells for Adoptive Immunotherapy. Nat Commun (2017) 8:15338. doi: 10.1038/ncomms15338

  • CrossRef
  • Google Scholar

• 90

  HuangXYangY. Driving an Improved CAR for Cancer Immunotherapy. J Clin Invest (2016) 126(8):2795–8. doi: 10.1172/JCI88959

  • CrossRef
  • Google Scholar

• 91

  ChenZJiZNgiowSFManneSCaiZHuangACet al. TCF-1-Centered Transcriptional Network Drives an Effector Versus Exhausted CD8 T Cell-Fate Decision. Immunity (2019) 51(5):840–55.e845. doi: 10.1016/j.immuni.2019.09.013

  • CrossRef
  • Google Scholar

• 92

  RaghuDXueHHMielkeLA. Control of Lymphocyte Fate, Infection, and Tumor Immunity by TCF-1. Trends Immunol (2019) 40(12):1149–62. doi: 10.1016/j.it.2019.10.006

  • CrossRef
  • Google Scholar

• 93

  HeQFXuYLiJHuangZMLiXHWangX. CD8+ T-Cell Exhaustion in Cancer: Mechanisms and New Area for Cancer Immunotherapy. Brief Funct Genomics (2019) 18(2):99–106. doi: 10.1093/bfgp/ely006

  • CrossRef
  • Google Scholar

• 94

  KurachiM. CD8(+) T Cell Exhaustion. Semin Immunopathol (2019) 41(3):327–37. doi: 10.1007/s00281-019-00744-5

  • CrossRef
  • Google Scholar

• 95

  SawantDVYanoHChikinaMZhangQLiaoMLiuCet al. Adaptive Plasticity of IL-10(+) and IL-35(+) Treg Cells Cooperatively Promotes Tumor T Cell Exhaustion. Nat Immunol (2019) 20(6):724–35. doi: 10.1038/s41590-019-0346-9

  • CrossRef
  • Google Scholar

• 96

  SiddiquiISchaeubleKChennupatiVFuertes MarracoSACalderon-CopeteSPais FerreiraDet al. Intratumoral Tcf1(+)PD-1(+)CD8(+) T Cells With Stem-Like Properties Promote Tumor Control in Response to Vaccination and Checkpoint Blockade Immunotherapy. Immunity (2019) 50(1):195–211.e110. doi: 10.1016/j.immuni.2018.12.021

  • CrossRef
  • Google Scholar

• 97

  DossetMJosephELRivera VargasTApetohL. Modulation of Determinant Factors to Improve Therapeutic Combinations With Immune Checkpoint Inhibitors. Cells (2020) 9(7):1727. doi: 10.3390/cells9071727

  • CrossRef
  • Google Scholar

• 98

  UtzschneiderDTGabrielSSChisangaDGlouryRGubserPMVasanthakumarAet al. Early Precursor T Cells Establish and Propagate T Cell Exhaustion in Chronic Infection. Nat Immunol (2020) 21(10):1256–66. doi: 10.1038/s41590-020-0760-z

  • CrossRef
  • Google Scholar

• 99

  SaeidiAZandiKCheokYYSaeidiHWongWFLeeCYQet al. T-Cell Exhaustion in Chronic Infections: Reversing the State of Exhaustion and Reinvigorating Optimal Protective Immune Responses. Front Immunol (2018) 9:2569. doi: 10.3389/fimmu.2018.02569

  • CrossRef
  • Google Scholar

• 100

  WoronieckaKChongsathidkietPRhodinKKemenyHDechantCFarberSHet al. T-Cell Exhaustion Signatures Vary With Tumor Type and Are Severe in Glioblastoma. Clin Cancer Res (2018) 24(17):4175–86. doi: 10.1158/1078-0432.CCR-17-1846

  • CrossRef
  • Google Scholar

• 101

  BlankCUHainingWNHeldWHoganPGKalliesALugliEet al. Defining 'T Cell Exhaustion'. Nat Rev Immunol (2019) 19(11):665–74. doi: 10.1038/s41577-019-0221-9

  • CrossRef
  • Google Scholar

• 102

  FribourgMAndersonLFischmanCCantarelliCPerinLLa MannaGet al. T-Cell Exhaustion Correlates With Improved Outcomes in Kidney Transplant Recipients. Kidney Int (2019) 96(2):436–49. doi: 10.1016/j.kint.2019.01.040

  • CrossRef
  • Google Scholar

• 103

  KimKParkSParkSYKimGParkSMChoJWet al. Single-Cell Transcriptome Analysis Reveals TOX as a Promoting Factor for T Cell Exhaustion and a Predictor for Anti-PD-1 Responses in Human Cancer. Genome Med (2020) 12(1):22. doi: 10.1186/s13073-020-00722-9

  • CrossRef
  • Google Scholar

• 104

  HeimKBinderBSagarWielandDHenselNLlewellyn-LaceySet al. TOX Defines the Degree of CD8+ T Cell Dysfunction in Distinct Phases of Chronic HBV Infection. Gut (2020) 70(8):1550–60. doi: 10.1136/gutjnl-2020-322404

  • CrossRef
  • Google Scholar

• 105

  SeoHChenJGonzalez-AvalosESamaniego-CastruitaDDasAWangYHet al. TOX and TOX2 Transcription Factors Cooperate With NR4A Transcription Factors to Impose CD8(+) T Cell Exhaustion. Proc Natl Acad Sci USA (2019) 116(25):12410–5. doi: 10.1073/pnas.1905675116

  • CrossRef
  • Google Scholar

• 106

  WangXHeQShenHXiaATianWYuWet al. TOX Promotes the Exhaustion of Antitumor CD8(+) T Cells by Preventing PD1 Degradation in Hepatocellular Carcinoma. J Hepatol (2019) 71(4):731–41. doi: 10.1016/j.jhep.2019.05.015

  • CrossRef
  • Google Scholar

• 107

  YaoCSunHWLaceyNEJiYMosemanEAShihHYet al. Single-Cell RNA-Seq Reveals TOX as a Key Regulator of CD8(+) T Cell Persistence in Chronic Infection. Nat Immunol (2019) 20(7):890–901. doi: 10.1038/s41590-019-0403-4

  • CrossRef
  • Google Scholar

• 108

  KhanOGilesJRMcDonaldSManneSNgiowSFPatelKPet al. TOX Transcriptionally and Epigenetically Programs CD8(+) T Cell Exhaustion. Nature (2019) 571(7764):211–8. doi: 10.1038/s41586-019-1325-x

  • CrossRef
  • Google Scholar

• 109

  Xu-MonetteZYZhouJYoungKH. PD-1 Expression and Clinical PD-1 Blockade in B-Cell Lymphomas. Blood (2018) 131(1):68–83. doi: 10.1182/blood-2017-07-740993

  • CrossRef
  • Google Scholar

• 110

  ZengZWeiFRenX. Exhausted T Cells and Epigenetic Status. Cancer Biol Med (2020) 17(4):923–36. doi: 10.20892/j.issn.2095-3941.2020.0338

  • CrossRef
  • Google Scholar

• 111

  BeltraJCManneSAbdel-HakeemMSKurachiMGilesJRChenZet al. Developmental Relationships of Four Exhausted CD8(+) T Cell Subsets Reveals Underlying Transcriptional and Epigenetic Landscape Control Mechanisms. Immunity (2020) 52(5):825–41.e828. doi: 10.1016/j.immuni.2020.04.014

  • CrossRef
  • Google Scholar

• 112

  CaiMCZhaoXCaoMMaPChenMWuJet al. T-Cell Exhaustion Interrelates With Immune Cytolytic Activity to Shape the Inflamed Tumor Microenvironment. J Pathol (2020) 251(2):147–59. doi: 10.1002/path.5435

  • CrossRef
  • Google Scholar

• 113

  Alvarez-FernandezCEscriba-GarciaLVidalSSierraJBrionesJ. A Short CD3/CD28 Costimulation Combined With IL-21 Enhance the Generation of Human Memory Stem T Cells for Adoptive Immunotherapy. J Transl Med (2016) 14(1):214. doi: 10.1186/s12967-016-0973-y

  • CrossRef
  • Google Scholar

• 114

  PilipowKScamardellaELugliE. Generating Stem-Like Memory T Cells With Antioxidants for Adoptive Cell Transfer Immunotherapy of Cancer. Methods Enzymol (2020) 631:137–58. doi: 10.1016/bs.mie.2019.08.016

  • CrossRef
  • Google Scholar

• 115

  TulucFSpitsinSTustinNBMurrayJBTustinR3rdSchankelLAet al. Decreased PD-1 Expression on CD8 Lymphocyte Subsets and Increase in CD8 Tscm Cells in Children With HIV Receiving Raltegravir. AIDS Res Hum Retroviruses (2017) 33(2):133–42. doi: 10.1089/AID.2016.0108

  • CrossRef
  • Google Scholar

• 116

  KalliesAZehnDUtzschneiderDT. Precursor Exhausted T Cells: Key to Successful Immunotherapy? Nat Rev Immunol (2020) 20(2):128–36. doi: 10.1038/s41577-019-0223-7

  • CrossRef
  • Google Scholar

• 117

  Terranova-BarberioMPawlowskaNDhawanMMoasserMChienAJMeliskoMEet al. Exhausted T Cell Signature Predicts Immunotherapy Response in ER-Positive Breast Cancer. Nat Commun (2020) 11(1):3584. doi: 10.1038/s41467-020-17414-y

  • CrossRef
  • Google Scholar

• 118

  VerdonDJMulazzaniMJenkinsMR. Cellular and Molecular Mechanisms of CD8(+) T Cell Differentiation, Dysfunction and Exhaustion. Int J Mol Sci (2020) 21(19):7357. doi: 10.3390/ijms21197357

  • CrossRef
  • Google Scholar

• 119

  KagoyaYNakatsugawaMYamashitaYOchiTGuoTAnczurowskiMet al. BET Bromodomain Inhibition Enhances T Cell Persistence and Function in Adoptive Immunotherapy Models. J Clin Invest (2016) 126(9):3479–94. doi: 10.1172/JCI86437

  • CrossRef
  • Google Scholar

• 120

  HeKLiuPXuLX. The Cryo-Thermal Therapy Eradicated Melanoma in Mice by Eliciting CD4(+) T-Cell-Mediated Antitumor Memory Immune Response. Cell Death Dis (2017) 8(3):e2703. doi: 10.1038/cddis.2017.125

  • CrossRef
  • Google Scholar

• 121

  AndersonKGStromnesIMGreenbergPD. Obstacles Posed by the Tumor Microenvironment to T Cell Activity: A Case for Synergistic Therapies. Cancer Cell (2017) 31(3):311–25. doi: 10.1016/j.ccell.2017.02.008

  • CrossRef
  • Google Scholar

• 122

  HeWZhangHHanFChenXLinRWangWet al. CD155T/TIGIT Signaling Regulates CD8(+) T-Cell Metabolism and Promotes Tumor Progression in Human Gastric Cancer. Cancer Res (2017) 77(22):6375–88. doi: 10.1158/0008-5472.CAN-17-0381

  • CrossRef
  • Google Scholar

• 123

  HashimotoMKamphorstAOImSJKissickHTPillaiRNRamalingamSSet al. CD8 T Cell Exhaustion in Chronic Infection and Cancer: Opportunities for Interventions. Annu Rev Med (2018) 69:301–18. doi: 10.1146/annurev-med-012017-043208

  • CrossRef
  • Google Scholar

• 124

  ChoiBDMausMVJuneCHSampsonJH. Immunotherapy for Glioblastoma: Adoptive T-Cell Strategies. Clin Cancer Res (2019) 25(7):2042–8. doi: 10.1158/1078-0432.CCR-18-1625

  • CrossRef
  • Google Scholar

• 125

  AtrashSBanoKHarrisonBAbdallahAO. CAR-T Treatment for Hematological Malignancies. J Investig Med (2020) 68(5):956–64. doi: 10.1136/jim-2020-001290

  • CrossRef
  • Google Scholar

• 126

  AbramsonJS. Anti-CD19 CAR T-Cell Therapy for B-Cell Non-Hodgkin Lymphoma. Transfus Med Rev (2020) 34(1):29–33. doi: 10.1016/j.tmrv.2019.08.003

  • CrossRef
  • Google Scholar

• 127

  KasakovskiDXuLLiY. T Cell Senescence and CAR-T Cell Exhaustion in Hematological Malignancies. J Hematol Oncol (2018) 11(1):91. doi: 10.1186/s13045-018-0629-x

  • CrossRef
  • Google Scholar

• 128

  BlaeschkeFStengerDKaeuferleTWillierSLotfiRKaiserADet al. Induction of a Central Memory and Stem Cell Memory Phenotype in Functionally Active CD4(+) and CD8(+) CAR T Cells Produced in an Automated Good Manufacturing Practice System for the Treatment of CD19(+) Acute Lymphoblastic Leukemia. Cancer Immunol Immunother (2018) 67(7):1053–66. doi: 10.1007/s00262-018-2155-7

  • CrossRef
  • Google Scholar

• 129

  GuanLLiXWeiJLiangZYangJWengXet al. Antigen-Specific CD8+ Memory Stem T Cells Generated From Human Peripheral Blood Effectively Eradicate Allogeneic Targets in Mice. Stem Cell Res Ther (2018) 9(1):337. doi: 10.1186/s13287-018-1080-1

  • CrossRef
  • Google Scholar

• 130

  HosokawaKMuranskiPFengXTownsleyDMLiuBKnickelbeinJet al. Memory Stem T Cells in Autoimmune Disease: High Frequency of Circulating CD8+ Memory Stem Cells in Acquired Aplastic Anemia. J Immunol (2016) 196(4):1568–78. doi: 10.4049/jimmunol.1501739

  • CrossRef
  • Google Scholar

• 131

  WangYWhittallTNeilSBrittonGMistryMRerks-NgarmSet al. A Novel Mechanism Linking Memory Stem Cells With Innate Immunity in Protection Against HIV-1 Infection. Sci Rep (2017) 7(1):1057. doi: 10.1038/s41598-017-01188-3

  • CrossRef
  • Google Scholar

• 132

  LeeYJParkJAKwonHChoiYSJungKCParkSHet al. Role of Stem Cell-Like Memory T Cells in Systemic Lupus Erythematosus. Arthritis Rheumatol (2018) 70(9):1459–69. doi: 10.1002/art.40524

  • CrossRef
  • Google Scholar

• 133

  Alvarez-FernandezCEscriba-GarciaLCaballeroACEscudero-LopezEUjaldon-MiroCMontserrat-TorresRet al. Memory Stem T Cells Modified With a Redesigned CD30-Chimeric Antigen Receptor Show an Enhanced Antitumor Effect in Hodgkin Lymphoma. Clin Transl Immunol (2021) 10(4):e1268. doi: 10.1002/cti2.1268

  • CrossRef
  • Google Scholar

• 134

  TeoYWBLinnYCGohYTLiSHoLP. Tumor Infiltrating Lymphocytes From Acute Myeloid Leukemia Marrow can be Reverted to CD45RA+ Central Memory State by Reactivation in SIP (Simulated Infective Protocol). Immunobiology (2019) 224(4):526–31. doi: 10.1016/j.imbio.2019.05.001

  • CrossRef
  • Google Scholar

• 135

  HoffmannJMSchubertMLWangLHuckelhovenASellnerLStockSet al. Differences in Expansion Potential of Naive Chimeric Antigen Receptor T Cells From Healthy Donors and Untreated Chronic Lymphocytic Leukemia Patients. Front Immunol (2017) 8:1956. doi: 10.3389/fimmu.2017.01956

  • CrossRef
  • Google Scholar

• 136

  LiuJZhongJFZhangXZhangC. Allogeneic CD19-CAR-T Cell Infusion After Allogeneic Hematopoietic Stem Cell Transplantation in B Cell Malignancies. J Hematol Oncol (2017) 10(1):35. doi: 10.1186/s13045-017-0405-3

  • CrossRef
  • Google Scholar

• 137

  MollanooriHShahrakiHRahmatiYTeimourianS. CRISPR/Cas9 and CAR-T Cell, Collaboration of Two Revolutionary Technologies in Cancer Immunotherapy, an Instruction for Successful Cancer Treatment. Hum Immunol (2018) 79(12):876–82. doi: 10.1016/j.humimm.2018.09.007

  • CrossRef
  • Google Scholar

• 138

  AgarwalSWeidnerTThalheimerFBBuchholzCJ. In Vivo Generated Human CAR T Cells Eradicate Tumor Cells. Oncoimmunology (2019) 8(12):e1671761. doi: 10.1080/2162402X.2019.1671761

  • CrossRef
  • Google Scholar

• 139

  BrudnoJNKochenderferJN. Recent Advances in CAR T-Cell Toxicity: Mechanisms, Manifestations and Management. Blood Rev (2019) 34:45–55. doi: 10.1016/j.blre.2018.11.002

  • CrossRef
  • Google Scholar

• 140

  BiascoLScalaSRicciLBDionisioFBaricordiCCalabriaAet al. In Vivo Tracking of T Cells in Humans Unveils Decade-Long Survival and Activity of Genetically Modified T Memory Stem Cells. Transl Med (2015) 7(273):273ra213. doi: 10.1126/sciimmunol.aay0555

  • CrossRef
  • Google Scholar

• 141

  JinLTaoHKarachiALongYHouAYNaMet al. CXCR1- or CXCR2-Modified CAR T Cells Co-Opt IL-8 for Maximal Antitumor Efficacy in Solid Tumors. Nat Commun (2019) 10(1):4016. doi: 10.1038/s41467-019-11869-4

  • CrossRef
  • Google Scholar

• 142

  ChoeJHWPBSimicMSGilbertRDLiAWKrasnowNAet al. SynNotch-CAR T Cells Overcome Challenges of Specificity, Heterogeneity, and Persistence in Treating Glioblastoma. Sci Transl Med (2021) 13(591):eabe7378. doi: 10.1126/scitranslmed.abe7378

  • CrossRef
  • Google Scholar

• 143

  PadgettLEDinhHQWuRGaddisDEAraujoDJWinkelsHet al. Naive CD8(+) T Cells Expressing CD95 Increase Human Cardiovascular Disease Severity. Arterioscler Thromb Vasc Biol (2020) 40(12):2845–59. doi: 10.1161/ATVBAHA.120.315106

  • CrossRef
  • Google Scholar

• 144

  FlynnJKGorryPR. Stem Memory T Cells (TSCM)-Their Role in Cancer and HIV Immunotherapies. Clin Transl Immunol (2014) 3(7):e20. doi: 10.1038/cti.2014.16

  • CrossRef
  • Google Scholar

• 145

  FlynnJKPaukovicsGCashinKBormKEllettARocheMet al. Quantifying Susceptibility of CD4+ Stem Memory T-Cells to Infection by Laboratory Adapted and Clinical HIV-1 Strains. Viruses (2014) 6(2):709–26. doi: 10.3390/v6020709

  • CrossRef
  • Google Scholar

• 146

  ChahroudiASilvestriGLichterfeldM. T Memory Stem Cells and HIV: A Long-Term Relationship. Curr HIV/AIDS Rep (2015) 12(1):33–40. doi: 10.1007/s11904-014-0246-4

  • CrossRef
  • Google Scholar

• 147

  CalascibettaFMicciLCarnathanDLawsonBVanderfordTHBosingerSEet al. Antiretroviral Therapy in Simian Immunodeficiency Virus-Infected Sooty Mangabeys: Implications for AIDS Pathogenesis. J Virol (2016) 90(16):7541–51. doi: 10.1128/JVI.00598-16

  • CrossRef
  • Google Scholar

• 148

  CartwrightEKPaleschDMavignerMPaiardiniMChahroudiASilvestriG. Initiation of Antiretroviral Therapy Restores CD4+ T Memory Stem Cell Homeostasis in Simian Immunodeficiency Virus-Infected Macaques. J Virol (2016) 90(15):6699–708. doi: 10.1128/JVI.00492-16

  • CrossRef
  • Google Scholar

• 149

  ViganoSNegronJOuyangZRosenbergESWalkerBDLichterfeldMet al. Prolonged Antiretroviral Therapy Preserves HIV-1-Specific CD8 T Cells With Stem Cell-Like Properties. J Virol (2015) 89(15):7829–40. doi: 10.1128/JVI.00789-15

  • CrossRef
  • Google Scholar

• 150

  LuXSongBWengWXiaHSuBWuHet al. CD4(+) T Memory Stem Cells Correlate With Disease Progression in Chronically HIV-1-Infected Patients. Viral Immunol (2017) 30(9):642–8. doi: 10.1089/vim.2017.0017

  • CrossRef
  • Google Scholar

• 151

  GuardoACZaramaAGonzalezTBargalloMERojasJMartinezEet al. Effects on Immune System and Viral Reservoir of a Short-Cycle Antiretroviral Therapy in Virologically Suppressed HIV-Positive Patients. AIDS (2019) 33(6):965–72. doi: 10.1097/QAD.0000000000002169

  • CrossRef
  • Google Scholar

• 152

  Munusamy PonnanSHayesPFernandezNThiruvengadamKPattabiramSNesakumarMet al. Evaluation of Antiviral T Cell Responses and TSCM Cells in Volunteers Enrolled in a Phase I HIV-1 Subtype C Prophylactic Vaccine Trial in India. PloS One (2020) 15(2):e0229461. doi: 10.1371/journal.pone.0229461

  • CrossRef
  • Google Scholar

• 153

  ManganaroLHongPHernandezMMArgyleDMulderLCFPotlaUet al. IL-15 Regulates Susceptibility of CD4(+) T Cells to HIV Infection. Proc Natl Acad Sci USA (2018) 115(41):E9659–67. doi: 10.1073/pnas.1806695115

  • CrossRef
  • Google Scholar

• 154

  UtayNSVigilKJSomasunderamAAulicinoPCSmulevitzBChiadikaSet al. Timing of Antiretroviral Therapy Initiation Determines Rectal Natural Killer Cell Populations. AIDS Res Hum Retroviruses (2020) 36(4):314–23. doi: 10.1089/AID.2019.0225

  • CrossRef
  • Google Scholar

• 155

  FinleyJ. Elimination of Cancer Stem Cells and Reactivation of Latent HIV-1 via AMPK Activation: Common Mechanism of Action Linking Inhibition of Tumorigenesis and the Potential Eradication of HIV-1. Med Hypotheses (2017) 104:133–46. doi: 10.1016/j.mehy.2017.05.032

  • CrossRef
  • Google Scholar

• 156

  FenwickCJooVJacquierPNotoABangaRPerreauMet al. T-Cell Exhaustion in HIV Infection. Immunol Rev (2019) 292(1):149–63. doi: 10.1111/imr.12823

  • CrossRef
  • Google Scholar

• 157

  SharovKS. HIV/SARS-CoV-2 Co-Infection: T Cell Profile, Cytokine Dynamics and Role of Exhausted Lymphocytes. Int J Infect Dis (2021) 102:163–9. doi: 10.1016/j.ijid.2020.10.049

  • CrossRef
  • Google Scholar

• 158

  ZhaoSXuWTuBHongWGZhangZChenWWet al. Alterations of the Frequency and Functions of Follicular Regulatory T Cells and Related Mechanisms in HIV Infection. J Infect (2020) 81(5):776–84. doi: 10.1016/j.jinf.2020.09.014

  • CrossRef
  • Google Scholar

• 159

  RoedererMQuayeLManginoMBeddallMHMahnkeYChattopadhyayPet al. The Genetic Architecture of the Human Immune System: A Bioresource for Autoimmunity and Disease Pathogenesis. Cell (2015) 161(2):387–403. doi: 10.1016/j.cell.2015.02.046

  • CrossRef
  • Google Scholar

• 160

  CianciottiBCRuggieroECampochiaroCOliveiraGMagnaniZIBaldiniMet al. CD4+ Memory Stem T Cells Recognizing Citrullinated Epitopes Are Expanded in Patients With Rheumatoid Arthritis and Sensitive to Tumor Necrosis Factor Blockade. Arthritis Rheumatol (2020) 72(4):565–75. doi: 10.1002/art.41157

  • CrossRef
  • Google Scholar

• 161

  LeeYJParkEHParkJWJungKCLeeEB. Proinflammatory Features of Stem Cell-Like Memory T Cells From Human Patients With Rheumatoid Arthritis. J Immunol (2021) 207(2):381–8. doi: 10.4049/jimmunol.2000814

  • CrossRef
  • Google Scholar

• 162

  CaoJZhangCHanXChengHChenWQiKet al. Emerging Role of Stem Cell Memory-Like T Cell in Immune Thrombocytopenia. Scand J Immunol (2019) 89(3):e12739. doi: 10.1111/sji.12739

  • CrossRef
  • Google Scholar

• 163

  BrideKLVincentTSmith-WhitleyKLambertMPBleesingJJSeifAEet al. Sirolimus Is Effective in Relapsed/Refractory Autoimmune Cytopenias: Results of a Prospective Multi-Institutional Trial. Blood (2016) 127(1):17–28. doi: 10.1182/blood-2015-07-657981

  • CrossRef
  • Google Scholar

• 164

  FlynnJKGorryPR. T Cell Therapies-are T Memory Stem Cells the Answer? Ann Transl Med (2015) 3(17):251. doi: 10.3978/j.issn.2305-5839.2015.08.13

  • CrossRef
  • Google Scholar

• 165

  MorrotA. Lifelong Protection Mediated by Stem Cell-Like CD8(+) T Memory Subset Cells (Tscm) Induced by Vaccination. Ann Transl Med (2016) 4(11):221. doi: 10.21037/atm.2016.05.38

  • CrossRef
  • Google Scholar