T-cell lymphoma (TCL) is a subclass of non-Hodgkin lymphoma (NHL) (1). The diagnosis and identification of risk factors associated with TCL are challenging due to the lower number of cases. TCLs cover a wide range of conditions that differ in disease progression and clinical symptoms. Broadly, TCLs are classified into peripheral T-cell lymphoma (PTCL) and cutaneous T-cell lymphoma (CTCL) (1) ( Table 1 ). TCLs account for only one-sixth of all NHLs, and most of them are of PTCL type (4). The basis of differentiation between PTCL and CTCL may be phenotypic, diagnostic, or prognostic (5). Over the years, this classification has been updated by the Revised European American Lymphoma (REAL) classification and the European Organization of Research and Treatment of Cancer (EORTC) (6). REAL is a WHO project which recently updated the categorization of tumors of lymphoid and hematopoietic origin (7). This updated classification identifies around 30 different types of PTCLs (7, 8). CTCL lymphomas are present on the skin with an absence of any subcutaneous symptoms at the time of diagnosis (6, 9). Clinically, CTCLs may have a slow or very aggressive mode of prognosis (6, 9, 10). Treatment and diagnosis of TCLs require a multidisciplinary approach inclusive of short-term or long treatment goals (9, 10).

With the recent advancement in the field of metabolomics or lipidomics, the understanding of cancer metabolism has increased. Developing tumors requires high energy and the macromolecule building block to support not only their proliferation but also the adaptation to changing environments during the process of metastasis (11–13). The Warburg effect along with increased glucose uptake is the characteristic metabolic feature of tumor cells (11–13). To fulfill these requirements, the cancer cell metabolism must be reprogrammed (13, 14). The activated T-cell metabolism resembles cancer cell metabolism up on activation through T-cell receptor signaling accompanied by co-stimulation through CD28 induction (15). To sustain this active state, IL-2-mediated signaling is a must (16). Similar to tumor cells, post-activation T cells divide rapidly much faster than any somatic cell (15, 17). Metabolically active T cells reprogram their metabolism to increase the uptake and utilization of glucose accompanied by changes in calcium flux with upregulated lactate production (18, 19). T-cell receptor (TCR)-mediated signaling starts glucose transport upregulation, but to attain the maximum metabolic reprogramming, CD28-mediated signaling must be activated (19, 20). In addition to TCR and costimulatory signaling, cytokine-mediated signaling is of utmost importance for the development of effector T cells, which resembles T-lymphoma cells metabolically (15, 21).

Irrespective of these metabolic similarities, the activated T cells rarely become cancerous, and once the immune challenges are over, the activated T cell either goes to apoptosis or attains the quiescent memory T-cell state (22–24). In the case of TCLs or other lymphomas, instead of going to apoptosis or resting memory cell state, the T lymphocyte remains in the state of hyperactivity due to gain-of-function mutation in the oncogene or loss of function of the tumor-suppressor gene (22, 25). This continuous state of proliferation is associated with altered metabolism in comparison with normal T cells (19, 25). Various reports associated the different genetic alternations in genes related to cytokine signaling with the pathogenesis of TCLs (25–30). Interactions between lymphoma cells and their microenvironment mediated by the altered cytokine profile of the tumor microenvironment (TME) disturb tissue homeostasis and thus favor lymphoma development and progression (31–34). The various aspects of T-cell lymphoma development like metastasis, migration, invasion apoptosis, and epithelial–mesenchymal transition (EMT) are regulated by the altered metabolic phenotype of T lymphoma cells and their abnormal interaction with other non-neoplastic cellular components of the TME (22, 24, 31). As with other solid and hematologic cancers, TCL progenesis depends upon the nature of tumor-infiltrating lymphocytes (TiLs). These TiLs are different from the original lymphoid organ immune cell and are predominantly T lymphocytes. It has been postulated that the interaction between TiLs and T lymphoma cells dictates the subsequent disease progression (35, 36). The TME is ever changing due to the entry of TiLs and subsequent inflammation associated with it (35–37). It has been reported that these TiLs induce inflammation and help in tumor cell survival (35).

For the proper functioning of the immune system, intercellular communication between immune cells is crucial. The important mediator of this immune communication is cytokine, a protein with low molecular weight. Cytokines are mainly secreted by immune cells and stromal cells and have a regulatory role in immune cell activation and subsequent differentiation, proliferation, and apoptosis (38). The role of cytokine in TCL progression is not very clear and depends upon the TME. The effect of cytokine may be either antitumor or malignancy promoting, which depends on the ratio of pro- and anti-inflammatory cytokines along with the level of expression of cytokine receptors present in the TME (39, 40). Since cytokines are a very important cog in the wheel of cellular communication, this review is aiming to discuss their role in the metabolism of T-cell lymphomas and the subsequent development of the tumor microenvironment.

The tumor cell microenvironment (TME) is a heterogenous body constituted of tumor cells, normal resident cells, infiltrating immune cells, extracellular matrix, and a variety of secreted mediators (31–34, 41, 42). The normal cells of the TME help in tumor promotion, and the intercellular communication inside the TME is mediated through the interwoven complex network involving various cytokines and enzymes, along with a plethora of growth factors (43–47). To understand the cancer disease mechanism, elucidation of this intercellular signaling is of utmost importance. T-cell lymphomas are generally highly proliferative and resistant to apoptosis and accumulate in the nodal and particular extranodal sites (48–51). Despite the general resistance to chemotherapy, culturing T-cell lymphoma cell lines for long is difficult because these cell lines are very prone to spontaneous apoptosis in in vitro conditions (52). These observations established the role of the TME in the pathogenesis of T-cell lymphomas (35–37). The TME is the main source of extrinsic growth, and the survival signal provided by the TME’s non-neoplastic cells including different hematopoietic (myeloid, lymphoid) and non-hematopoietic cells is essential for T-lymphoma survival (35–37) ( Figure 1 ). The source T-cell variant from which the tumorigenic T cell derives significantly dictates the composition of the TME (39, 42, 53, 54). As in the case of AITL (angio-immunoblastic T-cell lymphoma), the overexpression of follicular T helper cells (Tfh) associated with cell surface receptors (ICOS, PD-1, and CXCR-5) along with BCL-6 established that AITL tumorigenic cells originated from Tfh cells. The cytokines (CXCL13, LT-beta, and IL-21) influence the recruitment, functional polarization, and expansion of cells within the TME of AITL (49, 55–57). While B-cell recruitment in the TME is promoted by CXCL-13 and IL-21, recruitment of follicular dendrite cells has been promoted by LT-β (58–60). The unique expression portfolio of different subsets of T-lymphoma cells for the cell surface ligand, cytokines, and chemokines provides uniqueness to its respective TME (25, 37, 61). The uniqueness of the TME of different subtypes of TCL is regulated by unique transcription factors specific for each subset of T cells (36, 61–63).

Recently, it has been found that in non-Tfh-derived T-cell lymphomas like PTCL-NOS, gene regulators like t-bet, GATA-3, and FoxP3 regulate the differential expression of their target genes including those cytokines that regulate the constituents of the TME (64–66). These observations suggested that the cell of origin is a major factor behind the composition of the TME in developing T-cell lymphomas and established the importance of TCR-mediated signaling aided by co-stimulatory and cytokine signaling in transcriptional and posttranscriptional regulations of these master transcription factors (38). These signaling alternations subsequently result in the development of a specific TME, which is evident by the homology between the receptor profile of T-lymphoma cells and the T cells’ source of origin subtypes (53, 54). Subsequently, the constituents of the TME in turn influence the availability of ligands and cytokines which drive the T-cell lymphoma growth proliferation and survival.

As reviewed in the previous section, the role of various signaling pathways in the alternation of the TME especially cytokine-mediated signaling is crucial and these alternations result in the hypoxic condition and acidic environment in the TME, which is the hallmark of any cancer (11, 18). To overcome this hostile microenvironment, the TME normalizes oxygen level and ensures adequate nutrient supply by promoting angiogenesis through co-ordination between its various intrinsic and extrinsic factors (33, 34). The upregulation of aerobic glycolysis in cancer cells is one example of an intrinsic factor that resulted in the “Warburg effect”. The “Warburg effect” results in the upregulation of glycolysis along with enhanced lactate production even in inadequate availability of oxygen (11, 13, 15). This increased level of lactate, in turn, alters the extrinsic factors resulting in alteration in the extracellular matrix (ECM) and angiogenesis along with tumor invasion (18). It has been shown that oncogenes like C-Myc, KRAS, and PI3K regulated the uplifting of glycolysis rate by upregulating the expression of various proteins of the glycolytic pathway (32–34).

These oncogenes are also responsible for increased glutaminolysis, a hallmark of tumor metabolism which resulted in both ATP generation and synthesis of precursors for the biosynthesis of other macromolecules such as nucleic acid, proteins, and lipids (11, 18). Previously, due to misinterpretation of the “Warburg effect”, it had been postulated that in cancer cells, the mitochondrial oxidative phosphorylation gets defective but now the importance of the mitochondrial electron transport chain in tumor progression has been accepted as evident by intra-aperitive 13C tracing experiments in human suffering from brain and lung cancer (32, 33, 37, 181). In various cancer types, enzyme mutation is another important intrinsic factor (15). In acute myeloid leukemia, lower-level gliomas and secondary glioblastomas are associated with somatic mutation of isocitrate dehydrogenase-1 and -2 (IDH1 and IDH2), which results in the conversion of alpha-ketoglutarate (αKG) to D-2-hydroxyglutarate (D-2HG), subsequently altering the various alpha-KG-dependent deoxygenase (11, 13, 15, 182). In addition to that, tumor progression is supported by a mutation in either succinate dehydrogenase complex (SDH) or fumarate hydratase (FH) enzymes which have antitumor effects in hereditary tumor syndromes (183–185). Fumarate also triggers cell migration in endometrial cancer (185).

Naive T cells are metabolically similar to other cells and need IL-7 for the maintenance of their basal required metabolism (19). The naïve T cells are smaller in size and generally do not divide. Metabolically, they are highly oxidative and depend completely on the efficient metabolic breakdown of glucose and glutamine (13, 19, 20). In humans, these naive T cells have a comparatively longer life span ranging from months to years. This longer life of T cells is attributed to the continuous induction of IL-7 (22) and alteration in anti-apoptotic protein BCL-2 (B-cell lymphoma-2) which result in the prevention of apoptosis initiation. Upon activation, the metabolic portfolio of a T cell gets a very significant transformation (19, 20, 24). Once they are activated through the TCR and co-stimulatory signal, T cells require continuous IL-2-mediated signaling to maintain their activated state (38). All these signaling mechanisms like TCR-mediated, CD-28-mediated, or IL-2-mediated trigger different pathways to support the upregulated metabolism (19, 24, 38). To support the highly activated and proliferative state, the activated T cells increase the glucose uptake, and upon activation, changes in calcium flux and lactate production occur instantly in these immune cells (19, 24).

Although TCR signaling is needed for initiation of upregulation in glucose transportation, for maximum glucose uptake, CD-28-mediated signaling along with AKT pathway initiation is a must (186, 187). IL-2 produced by activated T cells maintains this upregulation in glucose transformation in an autocrine fashion (188–190). This increased uptake of glucose is accompanied by upregulated oxygen consumption, which is quite similar to the cancer cells (18, 19, 33, 188). Increased glucose uptake results in ATP generation through glycolysis as well as the production of precursors of nucleic acid, lipids, and antioxidants through the pentose phosphate pathway (PPP) (15, 20). These metabolic changes are dependent on cytokine stimulators (191). It has been reported that T regulatory cells are less glucose-dependent metabolically, and rather than this, they depend on fatty acid oxidation to support their metabolism (192, 193). It has been demonstrated that the naive cells activated without glucose do not develop into effectors cells but are easily differentiated into T cells (19). Recently, the role of hypoxia-inducible factor (HIF-1) in the development of Th-17 cells has been documented (194, 195). This underlying difference in metabolism between effector T cells and T-reg cells is very crucial to understanding TCL metabolism in the context of normal cell metabolism (15, 38). JAK-STAT and P13K-AKT downstream of the cytokine signaling pathway of T-cell activation are very crucial to maintaining the growth and proliferation of activated T cells (19, 191, 196). STAT is associated with the IL-2 receptor, and upon IL-2R binding with IL-2, it upregulates some proteins such as BCL-2, C-Myc, and cyclin D (188, 189). The P13K-AKT pathway is associated with the CD-28 co-stimulatory receptor and cytokine receptor in almost all cancer cells including TCL, and this pathway is activated in an inappropriate way (22, 38, 191). Phosphorylated AKT in TCL activates the mammalian target of rapamycin complex-1 (mTORC-1) to bring upregulation in protein translocation (197). The activated mTORC-1 deactivates protein synthesis inhibitor eIF4E binding protein to allow cap-dependent protein synthesis; furthermore, mTORC-I activates S-6 kinase resulting in Sb-ribosomal protein activation (198). The availability of free amino acid is critical to continuing the activity of mTORC-I, and this continued activation of mTORC-I ultimately results in the overrepresentation of glucose transporter-I (Glut-I) along with C-Myc and HIF-I alpha in TCL cells (199). The activation of Akt downstream to CD28 maintains the Glut-I expression on the cell surface and also helps in the upregulation of hexokinases for maximum utilization of glucose by the cell along with the activation of PPP to facilitate the synthesis of other macromolecule precursors (15, 20, 196, 200). This metabolic phenotype of activated T cells is different from other normal cells but similar to the TCL cells (93).

Mitochondrial membrane permeabilization is a crucial step to initiating apoptosis, and Akt activation through cytokine signaling has the ability of hexokinase localization which may hinder mitochondrial membrane permeabilization (201, 202). It has also been reported that activated Akt promotes ubiquitination of tumor-suppressive P⁵³ and subsequent degradation of P⁵³, which results in suppression of synthesis of the proapoptotic P⁵³-upregulated mediator of apoptosis (PUMA) protein (203, 204). A significant decrease in Puma accumulation inside the activated T cell, as well as T lymphoma cell, is associated with upregulation in glucose uptake and activation of Akt (201, 204). The changes in metabolic phenotype brought by upregulation in glucose uptake are also associated with the stability of anti-apoptotic protein myeloid cell leukemia-I inside the activated T cell and T lymphoma cell (205). This observation indicates that Akt and other signaling pathways inside activated T cells may result in anti-apoptotic signaling alternation (93).

As discussed above, the metabolic alternation observed in the activated T cells is very similar to T lymphoma cells ( Figure 3 ). It has been reported that many cancer cells including TCL upregulate the expression of the embryonic M2 isoform of pyruvate kinase (PKM 2) which results in the promotion of aerobic glycolysis and lactate production, bypassing the TCA cycle (206). An irregular expression of C-MYC or HIF-I alpha in tumorigenic T cells inactivates pyruvate dehydrogenase and upregulates lactate dehydrogenase A (LDHA), which promote the conversion of pyruvate to lactate (194). Recently, it has been reported that tumor cells like many activated lymphocytes use extracellular glutamine as a carbon source as well as a primary energy source, and this is linked to the inappropriate expression of C-MYC in mice (93, 207). Although T lymphoma cells are very similar to activated T cells, tumor cells have mutations in enzymes of the TCA cycle which is not the case with normal activated T lymphocytes (93). Examples are the mutations observed in isocitrate dehydrogenase (IDH) I and IDH 2 in gliomas and leukemias (208, 209). IDH is an important enzyme that regulates the conversion of isocitrate to alpha-keto-glutarate, and after mutation, they convert alpha-ketoglutarate to 2-hydroxyglutarate, a novel metabolite which subsequently alters the epigenome of the cell (208, 210).

The T lymphoma cell expresses muted versions of growth factor receptors and thus mimic the activated lymphocyte for their survival (93, 211). This is evident by the observation that in more than 50% of patients with T-cell acute lymphoblastic leukemia, proteins of the Notch pathway were mutated (212). The Notch pathway is very critical for the development and lineage selection of lymphocytes (213). As discussed, the expression of C-Myc is associated with upregulated glucose metabolism and mutations resulting in the overexpression of C-Myc have been reported in various lymphomas like Burkitt’s lymphoma (196). It can be concluded that these alternations in the signaling pattern of cancer cells including T lymphoma cells are the chief reason behind the Warburg phenotype and constitutive expression of Akt, along with C-Myc results in upregulation of aerobic glycolysis, inhibition of the TCA cycle (through the activation of proto-oncogene), and suppression of apoptotic genes. It has been clear that the metabolic reprogramming of tumor cells is essential for their survival and development. As discussed in this section, T-lymphoma cells mimic activated T cells metabolically, but the T-lymphoma cell differs from normally activated T cells because it expresses various oncogenes and inhibits tumor-suppressor genes. Due to this difference, whereas normally activated T cells either go through apoptosis or attain the state of anergy, T-lymphoma cells continue to survive and divide. To support this continuous growth, metabolic reprogramming is essential, which is also termed as the “Warburg effect”. For the effectiveness of the Warburg effect, signaling mediated by various cytokines is essential, as highlighted in this section. Various signaling pathways downstream of cytokine receptor-mediated signaling pathways like P13K-AKT and JAK-STAT are responsible for the pro-tumorigenic metabolic alternation. Cytokines like IL-7 and IL-2 have proven roles in the maintenance of basal metabolic requirements, and as discussed, their expression level is directly linked with metabolic reprogramming. Therefore, on the basis of the findings discussed in this section, it may be easily concluded that cell signaling alternations especially cytokine mediated are crucial for T-lymphoma cells’ metabolic reprogramming.

In the earlier section of this review, it has been discussed that the role of the cytokine in the TME development of the T-lymphoma cell and subsequent metabolic reprogramming to support the demanding metabolic requirement is crucial. The recent whole-exome signaling and gene expression profiling studies have shown that in T-cell lymphomas, all three signals (TCR signaling, co-stimulating signaling, and cytokine signaling) get altered (214, 215). In signal-1 in normal T cells, their T-cell receptor recognizes MHC-bound protein which subsequently activates the T cell through the downstream signaling via CD3 (186, 187). This interaction of TCR with the MHC-bonded peptide is very specific and sensitive. Mainly the kinases like LCK (lymphocyte-specific protein tyrosine kinase) and FYN are involved in the autophosphorylation of conserved immune-receptor tyrosine-based activation motifs (ITAMs) located in the cytoplasmic domain of the CD3 (216). These T-cell activation kinase domains get autophosphorylation by the SRC family kinase (SKFs), and dephosphorylation is mediated through several phosphates like phosphates of cytosol, protein tyrosine phosphatase non-receptor-6 (PTPN-6), PPTN22, CD45, and DUSP22 (dual-specificity phosphatase22) (216, 217). The inhibitory signal to the activation of this pathway is mediated by inhibitory C-terminal tyrosine which gets phosphorylated by CSK (C-terminal SRC kinase) and dephosphorylated by CD45 (217). LCK remains continuously active to maintain the signal required for the survival of naïve T cells (186). LCK activity along with ζ-chain activation via phosphorylation recruits ZAP70 (zeta-chain-associated protein kinase 70) and SYK family kinase, which results in the attainment of ZAP70 to its active conformation. This activation of ZAP70 results in the phosphorylation of adopter proteins like LAT (linker for activation of T cells) and SLP-76 (an SH2 domain-containing leucocyte protein of 76 kDa (186, 216) ( Figure 4 ). Thus, TCR-dependent signaling of T-cell activation is rather complex involving multiprotein signalosomes, which result in the activation of multiple signaling networks essential for T-cell activation. TCR expression on T lymphoma cells is intact with some exceptions (218, 219). It has been reported that in peripheral T-cell lymphomas not otherwise specified (PTCL, NOS), the elements of the TCR complex were intact in more than 85% of cases, along with a normal expression of ZAP-70, LAT, and ITK. These observations were also similar for angioimmunoblastic T cells which use this TCR-mediated signaling for their growth and survival (220). The required engagement with MHC/peptide to activate TCR-mediated signaling in T lymphoma cells may be provided by the TME of tumorigenic T cells (53). To support this, it has been observed that immature DCs and macrophage favor the T-cell tumor development in vitro, which can be inhibited by MHC-blocking antibodies or clonotypic TCR (108). It has not been clear whether antigen-independent TCR signaling occurs in T-cell lymphoma, but the role of TCR-mediated signaling is established through the study on mouse models. Wang et al. have shown that 100% PTCL is developed in mouse models if the TCR remains intact and functional (108, 221). The importance of TCR signaling in TCL is further supported by studies on the role of antigen drug-associated neo-antigen in the development of T-cell lymphoma (38, 220).

Although the role of CD3-TCR-mediated signaling in the development of T-cell lymphoma is universal, in many subtypes of PTCL, there are various alterations that result in TCR complex independent activation of downstream TCR signaling. The case of systemic anaplastic large cell lymphomas (ALCL), in which NPM-ALK (nucleophosmin-anaplastic lymphoma kinase) translocation fuses the catalytic domain of ALK with the dimerization domain of NPM, results in autophosphorylation of ALK resulting in activation of the pathways which are either redundant with RAS/RAF/ERK and P13K/STAT-3 pathway or complimentary to the JAK3/STAT3 pathway (38, 216, 222, 223). This ALK-dependent pathway may work as a substitute for TCR-independent downstream signaling activation (223). Although the mechanism is still not well elucidated, it has been reported that translocation involving the interferon regulatory factor (IRF)-4-DUSp22 (dual-specificity phosphatase 22) results in low expression of DUSP22 which can lead to the uninhibited activation of LCK and ERK and lead to the sustaining of downstream signaling induced by the TCR complex (224, 225). In approx. 20% of PTCL NOS, a translocation is observed between ITK and ZAP70 homologue SYK (226). This translocation results in the fusion of the pleckstrin and T homologous domain of ITK with the SYK kinase domain resulting in a catalytic fusion protein that can phosphorylate PLC- γ 1 , SLP-76, and LAT1 along with endogenous SYK (227). This unique ITK-SYK fusion protein induces SRC family kinase-independent mimics of TCR-mediated signaling cascades (224, 227). This fusion protein is reported to be an oncogenic and transgenic expression, causing lymphoproliferative disorder similar to the human PTCL in mouse models (226, 227). Mutation in the gene-specific TCR signaling has been reported in many T-cell lymphomas. One of the examples is a recurrent mutation in RHOA, a small GTPase protein that has been observed in approx. 70% AITL and around 20% of PTCL and NOS. This RHOA (RAS family protein) binds active GTP, and the mutation (G17V) in the GTP binding site of RHOA in T-cell progenitors present in the thymus results in the development of T-cell lymphoblast leukemia in mouse models (228–231). It has been reported that when dominant-negative RHOA (Gi7V) is transduced in the cell line, it results in altered F-actin stress fiber development (230–232). This actin cytoskeleton is crucial for proper TCR activation since it maintains the spatiotemporal integrity of the cell membrane (233, 234). Other important proteins crucial for regulating the actin cytoskeleton are E2H2 (polycomb group protein) and Vav1 (A guanine exchange factor) (233).

In addition to TCR-mediated signaling, additional non-MHC signaling is essential for the proper activation of T cells. Various co-stimulatory signaling receptors have been reported to belong to either the Ig superfamily or the TNF receptor superfamily (TNRSF) (235, 236). Along with this activator co-stimulatory receptor, there are numerous homologous receptors with inhibitory effects present on T cells enabling the maintenance of fine-tuning of T-cell-mediated immune response (235). These co-stimulatory receptors mediate the activation of different signaling pathways like P13K, MAPK, NFAT, and NF- K β (236). It has been observed that CD28 engagement induced the proliferation of Sézary cells (237). Recently, a recurrent mutation in both the intracellular and extracellular domains of the CD28 receptor is reported in some PTCL resulting in increased affinity of receptor CD28 to its corresponding ligands (238). These observations are suggestive of the role of CD28 co-stimulation in T-cell lymphoma pathogenesis. Furthermore, in Sézary syndrome patients, the fusion of the transmembrane and extracellular domains of CTLA-4 with the intracytoplasmic domain of CD28 has been reported, which results in upregulation in CD28 signaling (239). The abundant availability of CD28 ligands in the TME supports the growth and development of T-cell lymphomas (34).

Following the engagement of TCR and CD28, the expression of ICOS (inducible T-cell co-stimulator) was induced. A knockout experiment in mouse models indicated the important role of P13K in ICOS-dependent proliferation, differentiation, and activation of T cells (38, 240). Although ICOS is expressed in various types of T cells, it is present in the germinal center and essential for GC homeostasis (241). It has been reported that AITL which has been originated from Tfh cells highly expresses ICOS (242). Another co-stimulatory receptor is CD134 (ox40) which belongs to TNRSF that is induced after TCR engagement but is not expressed by either naive or memory T cells (243). The ligand of CD134 is expressed by professional antigen-presenting cells, active T cells, and some non-hematopoietic cells (244). After activation through its ligand, CD134 trimerizes and its recruitment in the lipid raft is followed by association with TNFR-associated factor (TRAF) proteins 2, 3, and 5 through a conserved motif present within its cytoplasmic tail (245, 246). CD134 is expressed in more than 95% of AITL, 17% in PTCL, and NOS and absent in anaplastic large cell lymphomas (ALCL) (247). Similarly, TNFRSF8 (CD30) is expressed in a variable manner in PTCL (248). Although the role of TNFRSF in T-cell lymphoma pathogenesis is poorly understood, the importance of TNFSFs in T-cell lymphoma is indicated by the fact that TNFRSFS homologous to B cells plays an important role in B-cell lymphoma pathogenesis (249).

Although MHC-peptide-dependent and co-stimulatory signals are crucial for the activation of naive T cells, cytokine-dependent signaling is essential for effective T-cell response. Various studies reported the important role of IL-12 and IFN-alpha/beta in CD8 T-cell maintenance and activation (38, 250). The signaling pathways of most of the cytokine receptors are induced by respective cytokine binding to its receptor followed by activation of a family of Janus kinases (JAK1, JAK2, JAK3, and tyrosine kinase-2), which is associated with the cytokine receptor cytoplasmic tail. Cytokine binding to its receptor results in conformational changes in JAKs which subsequently phosphorylate signal transducers and activators of transcription (STAT) monomer (38, 251). Activated STAT dimerizes and after translocation to the nucleus regulates the gene expression (251). In T-cell lymphoma, any cytokine that suppresses host anti-tumor activity is considered a tumor-promoting cytokine. It has been reported that various inflammatory and homeostasis cytokines have a role in T-cell lymphoma pathogenesis (38, 87). Transcription factor GATA-3 is a master regulator of Th2 differentiation since it binds to the locus of Th2-specific cytokines. Two dominant subclasses of cytokines have been reported in the case of PTCL: one is GATA-3 enriched (IL-4, IL-5, IL-13), and another is t-bet enriched (IFN-gamma and IFN-gamma inducible gene). In the PTCL, NOS and the GATA-3+ subclass of T-cell lymphomas resembled CTCL on a molecular level in which type 2 cytokines have a direct role in the proliferation and survival of tumor cells. IL-5-dependent hypereosinophilia has been observed in the GATA 3+ subclass of PTCL (64, 252). Recent whole-genome and whole-exome studies have reported that recurrent mutations in JAK and STAT genes are frequent in some classes of T-cell lymphomas (70). For example, in T-cell polympholytic leukemia (T-PLL), recurring mutation in gamma-chain, JAK1, JAK3, and STAT has been reported in more than 75% of cases (253–255). Similarly, STAT5b mutation is frequent in gamma F-PTCL and NK-cell-derived lymphomas (255). Although STAT3 mutation is not very prevalent, it has an important role in indolent T-cell lymphoproliferative disorders (256). It has also been reported that the PTPRK (receptor type tyrosine-protein phosphatase K) gene located at chromosome 6q is mostly deleted in extranodal NK-cell lymphoma and T-cell lymphoma, which results in STAT3 dephosphorylation and subsequent activation of STAT3 in approx. 50% of NK/T-cell lymphoma (257). It has been observed that JAK/STAT mutation is more prevalent in TCL than recurring mutation in its cytokine receptors (258). Mutation in chemokine receptor CCR4 is an exception, which is more frequent in TCL (259). The c-terminal truncating recurring mutation in CCR4 is reported in more than 25% of ATLL cases (260). This mutation in CCR4 hinders its internalization, a kind of gain-of-function mutation, and it was reported to be associated with increased PI3K/Akt activation which in turn plays a crucial role in metabolic reprogramming in TCL (260, 261).

It is easy to describe the role of these different T-cell signaling pathways in TCL pathogenesis in isolation, but in actuality, all these signaling pathways are interwoven and regulate the TCL pathogenesis in a coordinated manner. The cross-talk between these signaling receptors has been observed, and their dependency on each other in TCL development and progression has been reported. However, it is a fact that alternation in TCR-mediated signaling is crucial to bringing required changes in other receptor signaling pathways for the survival of T-lymphoma cells. Through the earlier works discussed in this section, it has been clear that in addition to metabolic alternation, cytokine-mediated signaling is also important for the overall development of T-lymphoma cells. Signaling mediated by these cytokines regulates the different stages of development, i.e., from naive T-cell to activated T-cell. In fact, all three T-cell signaling pathways, i.e., TCR mediated, co-stimulatory, and cytokine-mediated, play a crucial role in TCL, which helps in the differentiation of T-lymphoma cells to attain its tumorigenic morphology and physiology. Cytokine-mediated signaling depends upon the various intrinsic and extrinsic factors, and it may be easily concluded that cytokine plays an important role in deciding the fate of the developing T-cell lymphoma in the tumor microenvironment.

Metabolism and immune response are interlinked, and as discussed in earlier sections, metabolic alternation is the hallmark of the tumor cell and this metabolic reprogramming in mammalian immune cells is a crucial immunological adaption to mounting a proper immune response (22). This association of metabolism with immune response has been known for the last 60 years (19, 23) ( Figure 5 ). It has been reported that IL-6, a pro-inflammatory cytokine, can regulate glucose as well as lipid metabolism (262). It is a fact that increased uptake of amino acid is crucial to support continuous mTOR activity and, along with C-Myc expression, IL-2 signaling plays a significant role in this (191, 198). It has been reported that IL-2 signaling induces amino acid transporter SLC7A5 and it redirects T-cell metabolic reprogramming through pyruvate dehydrogenase kinase (PDK)-mediated upregulation of mTOR, which does not require P13K/AKT signaling in CD8+ T cells (191, 198, 263). The role of IL-2 in Treg-cell metabolism regulation is evident by the high expression of the IL-2 receptor (IL-2R), which is accompanied by the phenotypic and functionally active state of Treg cells (189, 264). IL-2-mediated signaling is crucial for T-cell metabolism as it co-ordinates P13K/AKT/mTOR activity, upregulates SLC7A5 expression, and upregulates C-Myc expression in CD4+T cells and CD8+ T cells (60, 189, 198). To support functionally active Treg cell metabolism, a continuous level of glycolysis and lipid biosynthesis along with the proper mitochondrial function is required and IL-2 has been reported to play an important role in all of these metabolic requirements of Treg cells (198, 265, 266). Another important cytokine for the maintenance of T-cell metabolic homeostasis is IL-7. It has been reported that IL-7-mediated signaling plays a crucial role in sustaining glycolysis in T cells through STAT-5-mediated AKT induction. It also induces GLUT1 expression in CD8+ memory T cells and IL-7 involved in triglyceride synthesis through increasing the rate of glycol uptake (198, 267).

IL-15 is essential for memory T-cell development, which alters the metabolism of these developing cells through the remodeling of cristae, a fusion of mitochondria, and upregulation in mitochondrial spare respiratory capacity (SRC) (268). IL-15 also supports fatty acid oxidation (FAO) through the upregulation of carnitine O-palmitoyltransferase-1 (CPT1a) which facilitate the transfer of the acyl group of long-chain fatty acyl-CoA from coenzyme A to 1-carnitine. It has been reported that IFN-α, which is an inducer of IL-15, can further upregulate transcription of antioxidant molecules like glutathione reductase, thioredoxin reductase, superoxide dismutase, and peroxiredoxin resulting in the long life of these memory cells (189, 191, 268, 269). This effect of IL-15 may be due to the neutralization of a high level of RO generated through the hyperoxidative phosphorylation activity of mitochondria by these antioxidant molecules. IL-15 plays an important role in the development of the tissue-resident population of T cells by promoting the mTOR activity in memory CD8+ T cells resulting in fastened activation and proliferation of CD8+ T cells in case of reinfection (191, 199, 268, 270). It has been reported that IL-21 has an important role in T-cell metabolism since it promotes fatty acid oxidation, antioxidant production, and mitochondrial biogenesis. It has also been reported that IL-21 has a role in promoting mTOR activity in Treg cells. It has been shown that priming of T cells with IL-21 and IL-15 before using in cancer T-cell therapy prolongs the life of these therapeutic T cells in a cancer mouse model (271–274). Studies have reported that by upregulating mitochondrial activity and reduction in oxidative stress in T cells, both IL-15 and IL-21 delayed the expression of apoptosis markers such as PD1 and LAG-3 (274, 275).

Although the role of inflammatory cytokines in T-cell metabolism has not been investigated much, evidence is growing which is suggestive of the roles of inflammatory cytokines in the alteration of T-cell metabolism (191) ( Table 2 ). A study has shown that IFN-γ can sustain the production of effector CD8+ T cells despite of a weak TCR signal (301). This effect of IFN-γ is through the activation of mTOR via STAT-1. The roles of IL-1β and IL-23 are crucial for the shifting of the Treg/Th17 axis toward Th17 through the promotion of human Th17 CD4+T cells. IL-1β-mediated signaling triggers HIF-1α expression along with upregulation of glycolysis-related genes like GLUT1 and HK2 (302–304). This further shift analysis suggested that IL-1β upregulates Th17 cell glycolysis. IL-23 has a synergistic effect on Th-17 cell differentiation and IL-23 is considered as the chief architect behind the Th17 cell phenotype (303). There are various phosphorylation targets on IL-23 identified through phosphor-proteomics analysis including an important glycolytic enzyme PKM2 whose upregulation results in hyperphosphorylation of STAT3 resulting in metabolic alternations (304, 305). It has also been reported that PKM2 is crucial for the homeostasis of the metabolism of Th17 cells (304). It has been observed that these effects of IL-23 can be inhibited by CD28 signaling, which also upregulates SIGIR expression in differentiating Th17 cells, resulting in the limitation of mTOR signaling (306, 307).

The TNF-α-mediated signaling inhibits CD4+ T-cell maturation and supports those cells which express anti-inflammatory cytokine IL-10 (308). Various studies have shown the role of TNF-α in calcium signaling which control T-cell metabolism. There is a recent report on the impact of TNF-α on the metabolic profile of CD4+ T-cells, but further studies are needed to fully elucidate the role of TNF-α in cellular metabolism in general and of T cells in particular (308–310). Although IL-10 has been reported to have a role in B-cell and macrophage metabolism alternation, evidence for the role of this anti-inflammatory cytokine in T-cell metabolism is few (280). TGF-β induced Smad-3-mediated inhibition of PI3K/Akt signaling in CD4+T cells, which results in the downregulation of important components of glycolysis like GIUT1 and HK2 (280, 298). Due to its suppressive effect on mTOR signaling, TGF-β favors T cells toward the inducible Treg phenotype. A study has reported that circulating Treg treated with TGF-β reduced the suppressive capacity of these Tregs through inhibition of glycolysis via the PI3K/AKT mTOR pathway (311). One in vitro study has shown that the presence of TGF-β in the tumor microenvironment can reduce OXPHOS in effector CD4+ T cells (299). Although there is growing evidence that cytokines play an important role in the reprogramming of T-cell metabolism, in turn, this metabolic alternation changes the cytokine profile of T-lymphoma cells as well as of the TME. Further studies are required to understand the mechanism behind cytokine-mediated metabolic reprogramming. As reported and summarized in this section, the cytokine-mediated signaling is important for metabolic reprogramming, and in turn, this metabolic alternation further changes the cytokine milieu of the tumor cell microenvironment in favor of T-lymphoma cell development and survival.

This is a matter of fact that cytokine receptor-mediated signaling is very crucial to the development and survival of tumor cells. With the advancement in tools and techniques, various novel biomarkers have been identified for the early diagnosis and prognosis of cancer. These biomarkers are a different class of biomolecules, and usually, cancer biomarkers are the molecules derived from the tumor cell and an ideal cancer biomarker should help in screening, prognosis, and cancer stage prediction as well as monitoring of treatment efficacy (312, 313). Another important criterion to be a good biomarker is that techniques based upon these biomarkers should be easy to handle, cost-effective, and reproducible (313). The currently approved biomarker for cancer has limited utility due to its low specificity and sensitivity (314). As cytokines have been associated with every stage of cancer development, these signaling mediators have great potential as a cancer biomarker (315, 316). Usually, a low amount of cytokines exists locally, but the upregulation in the cytokine level is observed in various abnormal conditions including tumors. The potential of cytokine as a biomarker is good because in tumors, the level of cytokines is related with tumor progression and changes in their expression level can be easily detected in body fluid mostly in the blood (317). The level of cytokines such as IL-6, IL-10, IL-8, TNF- α , and VEGF can be co-related with disease progression in ovarian, breast, and cervical carcinoma (317, 318). As discussed in the various sections of this review, the level of cytokine is clearly associated with T-lymphoma progression and metabolic rewiring required for the survival of T-lymphoma cells. As mentioned in Tables 1 , 2 , various cytokines and their expression level influence the metabolic alternation in T-lymphoma cells. Some more obvious cytokines such as IL-2, IL-6, IL-7, and IL-15 have a direct link with T-cell lymphoma progression, and these cytokines’ expression levels have the potential to be used as biomarkers especially to predict the developmental stage of T-lymphoma tumor cells.

Despite of this clear co-relation, the main hindrance in using cytokines as a biomarker is that cytokines are mechanism specific, not tumor specific. In recent times, numerous works have been reported which evaluated the potential of cytokines as a cancer biomarker, but mostly, these studies evaluate cytokines in isolation; however, in reality, the cytokine expression depends upon various interwoven factors (319–322). The potential of cytokine as an independent biomarker will be realized through the elucidation of the interwoven factors affecting the cytokine level in specific conditions. Another problem in using cytokine as a biomarker is to decide the cutoff value, which is essential to using any biomarker as a diagnostic tool. In the case of cytokine, it is really a huge challenge to differentiate between normal levels and abnormal levels of cytokine because only few studies have been done under any particular condition to decide the base-level value of any particular cytokine to use as a biomarker for any cancer including T-cell lymphoma. Due to the advent of multiplex arrays nowadays, it is possible to monitor the level of different cytokines simultaneously and then use these cytokines as a biomarker group. The receiver operating characteristics analysis (ROC analysis) which is based upon the plot of the true positive rate versus false positive rate of a particular disease at various cutoff may be helpful in deciding the cutoff value of cytokine to enable them to be used as a biomarker (323). In addition, in infectious disease where the roles of cytokines are more clear, the diagnostic potential of cytokines has been established in certain chronic conditions like Alzheimer’s disease (AD) and tumors. A recent study conducted on Malaysian people reveals the clear-cut link between blood IP-10 (interferon gamma inducible protein 10) along with IL-13. The level of these anti-inflammatory mediators was found to be on the lower side in AD subjects in comparison with healthy control significantly (324). Similarly, cytokines such as IL-6 and IL-8 are associated with poor neurological outcomes in individuals who experienced cardiac arrest. The cutoff value to predict poor neurological progress is 1423 pg/ml for IL-8 and 2708 pg/ml for IL-6 with 100% sensitivity and 86% specificity (325). The 1.97-pg/ml serum level of IL-6 with 81.8% sensitivity and 66.7% specificity is found to be the optimal diagnostic cutoff for gastric cancer (326). Two cutoff values, i.e., 400 pg/ml (92% sensitivity and 60% specificity) and 1,200 pg/ml (84% sensitivity and 87%), for IL-6 has been evaluated for stage I and stage II ovarian cancer subjects. The VEGF diagnostic cutoff was found to be 90% sensitive and 80% specific at the serum level value of 400 pg/ml (327). Many studies have been reported with a moderate rate of success to establish the cytokine as a diagnostic or prognostic biomarker. It is clear that to establish the cytokine as a biomarker for T-cell lymphoma development, a particular cutoff value is needed to be identified, and for this, elucidation of complex cytokine biology is needed. The ROC analysis will help in this regard, but the sample size needs to be sufficiently high to draw any conclusion. However, due to a limited number of cases, it is really difficult to find a cutoff value of cytokines to be established as a diagnostic or prognostic marker. The development of an animal model is an alternative to solve this problem and requires a high degree of attention of researchers working in the area. However, despite these limitations, cytokine has certain usefulness as a supportive biomarker to predict the T-lymphoma cell progression and diagnosis. These cytokines may be used as a corroborative marker along with other clinical symptoms and outcomes to estimate the treatment responsiveness and disease progression, but certainly, it warrants more attention from clinicians and researchers.

As of other cancer cells, the classical T-cell lymphoma TME constitutes various immune-active non-neoplastic cells like lymphocytes, mast cells, macrophages, and eosinophils. These cells may even outnumber the neoplastic cells (31–33). Although the biology of real interaction between the T-lymphoma cells and other cells of the TME is not fully elucidated, the role of cytokine-mediated signaling is getting much attention (35). T-lymphoma cells undergo metabolic alternation to fulfill the ever-increasing demand of ATP, NADH, and NADPH bio-synthesis to support their growth and proliferation. It has been established that in T-cell lymphomas as with other cancers, all the neoplastic cells are not in the same state metabolically (31, 39). The ever-changing TME exerts selective pressure on T-lymphoma cells. Due to the Warburg effect, tumor cells release an increasing amount of lactate in the tumor microenvironment resulting in acidosis and hypoxia (328). Cytokines play an important role in the development of the TME and metabolic reprogramming in T-cell lymphoma (40, 43, 87). The cytokine milieu of the TME dictates the tumor progression, and mutation in cytokine signaling protein significantly favors the tumor development. In addition, TCR- and CD28-mediated signaling and cytokine receptor signaling are very crucial for proper T-cell activation and proliferation. Cytokines like IL-2 and IL-7 are well-established mediators of T-cell lymphoma metabolic reprogramming (38, 60, 277). Alternation in downstream signaling of cytokine receptors has been reported in various types of T-cell lymphomas, which has been discussed in the various sections of the review. The specific mutation in the AKT-P13K and JAK/STAT pathways associated with cytokine receptors has been reported. These alternations ultimately lead to much-needed changes in metabolism to sustain tumor growth and proliferation. Apart from metabolic reprogramming, cytokine-mediated signaling plays an important role in the overall cellular compositions of the TME, as discussed in various sections of this review. T-cell lymphoma development depends upon various extrinsic as well as intrinsic factors, and cytokines have certainly an important role in coordinating these extrinsic and intrinsic factors resulting in T-cell lymphoma development and progression. The cytokines released from different tumor-infiltrating lymphocytes have an important role in the cross-talk between T-lymphomas and their corresponding TME (35). Although T-lymphoma cells resemble metabolically activated T cells, the mutation in the genes related to cytokine signaling has been observed in the development of almost all subtypes of T-cell lymphomas. Thus, the importance of cytokine milieus of the TME in T-lymphoma progression is further needed to be explored for developing a new therapeutic target against T-cell lymphomas. Elucidation of the role of cytokine in tumor development will help in finding T-lymphoma-specific biomarkers for early diagnosis of T-lymphoma and to monitor the disease progression along with in follow-up to the treatment response.

Corresponding and joint first authors from Guru Ghasidas Vishwavidyalaya wrote and edited the manuscript. All other co-authors contributed intellectually to the designing, editing, and proofreading of the manuscript. All authors contributed to the article and approved the submitted version.