HDACs have been reported to be necessary for t cell development. CD4 lineage integrity is regulated by HDAC1 and HDAC2 members through downregulation of Runx3/CBFβ complexes, which induce CD8 lineage programs in CD4 + t cells (Boucheron et al., 2014; Ellmeier, 2015). An HDAC1 and HDAC2 knockout test of t lymphocytes also has been found to result in cell cycle arrest and reduction of thymocytes. These events will eventually lead to decrease of the peripheral t cells and appearance of CD4 + and CD8 + t cells (Preglej et al., 2020). Another experiment with knockout HDAC1 and HDAC2 in mice showed the HDAC1/2-Sin3A-NuRD complex is disrupted. This may block double-negative (DN) to double-positive (DP) transition, and failure of proliferation. Moreover, insufficiency of HDAC1 or HDAC2 may lead to overacetylation of histones and chromosomal instability, finally causing t cell lymphoma (Dovey et al., 2013). Above all, this research indicates that HDAC1 and HDAC2 are essential for t cell development.

HDAC3 has also been found to be indispensable in steps of t cell progression, including commitment of CD4 and CD8, positive selection, and peripheral t cell maturation (Wang P. et al., 2020). HDAC3 deficiency in DP thymocytes terminates CD4-lineage program and redirects the MHC class II-restricted thymocytes toward the CD8-lineage program, due to the acetylation of histone expressing CD8-lineage genes, such as Runx3 and Patz1 (Philips et al., 2019). In a CD2-icre HDAC3 conditional knockout (HDAC3-cKO) mice, t cell development is blocked at the positive selection step, resulting in fewer CD4 and CD8 T cells, and cannot be rescued by TCR-transgene. The absence of HDAC3 renders RORγt unable to down-regulate although positively selected and fails to upregulate Bcl-2, which may lead to apoptosis (Philips et al., 2016). For t cell maturation, HDAC3 forms complexes with NF-kappaB-activating-protein (NKAP), which is necessary for recent thymic emigrants (RTE) to gain functional competency and transfer into a long-lived naive t cell pool. Lack of HDAC3 may cause CD50 downregulation which leads to t cell immaturation. In peripheral T cells, HDAC3 deficiency creates a defect in TNF licensing after TCR/CD28 stimulation (Hsu et al., 2015). Another distinct subset of t cells, nature killer t (NKT) cells, are also HDAC3 dependent during development. As was previously mentioned, NKAP activated through formation of complexes with HDAC3, also participates in invariant NKT (iNKT) cells lineage. Furthermore, HDAC3-deficient iNKT cells show low expression of nutrient receptors GLUT1, CD71 and CD98, and this results in incremental autophagy (Thapa et al., 2016, 2017).

Class IIa HDACs are also involved in t cell development. HDAC5 is implicated in t-regulatory (treg) cells homeostasis. In an HDAC5^–/– mice model, T_reg cells show reduced suppressive function, CD4 + t cells convert poorly into treg cells, and increasing acetylation of Foxo1 causes treg cells to experience difficulty in maintenance of the phenotype. CD8 + t cells have found to be less able to produce IFN-γ in HDAC5^–/– mice (Xiao et al., 2016). HDAC7, a thymus-specific HDAC, acts as a regulator of t cell apoptosis and endothelial cell functions, is highly expressed in DP thymocytes, and inhibits Nur77 that is involved in apoptosis and negative selection. During TCR activation, HDAC7 is exported from the nucleus, leading to Nur77 expression and mediating TCR-mediated apoptosis (Dequiedt et al., 2003; Martin et al., 2008). HDAC6, a class IIb member of the HDACs, controls the production of immunosuppressive cytokine IL-10, and induction of antigen-presenting cells (APCs) that activate antigen-specific naïve t cells through formation of a complex with STAT3 (Cheng et al., 2014). HDAC10, another class IIb HDAC, mediates the inactivation of Foxp3. Foxp3 + treg cells are known to suppress immune responses, and HDAC10 dysfunction may cause some inflammatory disorders (Dahiya et al., 2020). HDAC11, which is the only member of class IV, negatively regulates the expression of IL-10. Overexpression of IL-10 will induce inflammatory APCs, priming naïve t cells and restoring the responsiveness of tolerant CD4 + t cells. Its adjustment with HDAC6 determines t cell activation (Villagra et al., 2009). HDAC11 acts as a positive controller of Foxp3 + tregs, and lack of HDAC11 will increase Foxp3 and TGF-β expression, which may lead to inflammation. The dynamic interaction between HDAC10 and HDAC11 serves to balance the immune response (Huang et al., 2017).

Investigating the elaboration of HDACs in t cell lymphoma would assist an understanding of their pathogenesis, prognosis and role as a therapeutic target. Although the precise mechanism underlying this behavior has not been elucidated, it can be investigated through HDACIs.

Gene expression that mediates a balance between HAT and HDAC histone modification is important because it is also marks initiation and progression of cancer cells. HDACs intervene in carcinogenesis through the deacetylation of histone and non-histone proteins (Jenuwein and Allis, 2001). Recent research has shown that HDACs are involved in the expression of numerous oncogenes such as Bcl- xL-, BCL2-, c-Myc, TCRβ and Notch3 (Palermo et al., 2012; Kunami et al., 2014; Loosveld et al., 2014; Stengel et al., 2015). HDACs also participate in cytokine regulation. In the study of cutaneous t-cell lymphoma (CTCL) patients, 30% demonstrated the high affinity of the IL-2 receptor, which can be perturbed by HDACIs (Shao et al., 2002). Furthermore, HDAC1 and HDAC6 were also found to be upregulated in CTCL. This causes excessive secretion of IL-15, which mediates the inflammation that is crucial in CTCL, suggesting this oncogenic loop can be controlled by modulation of HDAC1 and HDAC6 (Mishra et al., 2016).

In t cell malignancies, HDACs act as negative controllers of apoptosis, and upregulation of HDACs will silence the pro-apoptotic gene and Bcl2 family expression. During the signaling pathway, HDACs can acetylate the chaperone heat shock protein 90 (HSP90), which stabilizes the client proteins RASGRP1 and c-RAF. These client proteins activate the mitogen-activated pathway, leading to the down regulation of the Bcl2 family (Ding et al., 2017). Upon treatment of peripheral t cell lymphoma with HDACi, chidamide induces cell apoptosis by downregulating Bcl2 and upregulating Caspase3 and Bax protein (Lu et al., 2016). The expression of a tumor suppressor gene was also found to be modulated by HDACs in CTCL cell lines. A combination of an HDACI, romidepsin and a demethylating agent, azacitidine leads to the induction of RHoB, the tumor suppressor gene, and to cell apoptosis (Rozati et al., 2016). The downstream apoptotic pathway regulated by HDACs may serve as a potent therapeutic target for apoptosis induction in a treatment for t cell malignancies (Figure 1).

Another self-devouring process similar to apoptosis is the source of dysfunction in t cell malignancies. Besides deacetylation of lysine residues in the histone, HDACs also have functions in regulation of cytosolic proteins which have a variety of cellular functions, including autophagy. SAHA (vorinostat), a pan-HDAC inhibitor, upregulates the expression of an autophagic factor LC3, inhibiting mTOR, the mammalian target of rapamycin and leading to activation of the autophagic protein kinase ULK1 (Figure 1; Gammoh et al., 2006). HDACs are inseparable by autophagy in cellular survival, and targeting autophagy by inhibition of HDACs could offer an effective treatment for t cell lymphomas.

The main function of HDACIs might be interference with histone and chromatin modification, but acetylation of histone and non-histone proteins may cause DNA damage, expression of suppressing genes in oncogenesis, and either lowering of the apoptotic threshold, or triggering autophagy response. These physiological processes have proved to be indispensable for HDACs in cancer pathogenesis and prognosis, and this makes them a prospective target for t cell malignancies.

Recently, HDACIs has been approved for TCL treatment, and most of them belongs to pan-inhibitor, such as vorinostat and belinostat. Indeed, these pan-HDAC inhibitors brought effectiveness in PTCL patients, but not in CTCL patients. Interestingly, romidepsin, a class I HDACs selective inhibitor, showed promising result in CTCL patients. Above all, inhibition of other HDAC subtypes would decrease the efficacy in CTCL, which inspired us targeting class I HDACs might increase the application of HDACI in TCL therapies. Moreover, romidepsin also showed broader availability comparing to other pan-HDACIs in combination with other target therapies or chemotherapies. Thus, further pre-clinical studies are necessary to understand the precise mechanism.

In B cell differentiation, HDAC1 and HDAC2 promote the development in the pre-B cell stage that progresses the cell cycle from G1 to S. Knockout of HDAC1 and HDAC2 leads to cell cycle arrest and expression of p21 and p57, which may cause apoptosis (Yamaguchi et al., 2010). At the terminal stage of B cell development, Blimp-1 restrains c-myc through the aggregation of HDAC1 and HDAC2 (Yu et al., 2000). In HDAC3 knockdown mice, the progenitor B cells cause impaired B cell maturation, and defects in VDJ (varies, diversity, joining) recombination (Stengel et al., 2017). HDACs participate in complex formation in different stages of B cell development. HDACs have been considered to be a component of the STAT5a-LSD1 complex, which demonstrates the possible activation of STAT5a in the early stages of B cell development (Nanou et al., 2017). In mature B cells, Bach2 recruits the HDAC3-NCoR1/NCoR2-Rif1 complex to repress Pdm1 transcription thus blocking the differentiation between B cells and plasma cells (Tanaka et al., 2016).

BCL6, a sequence-specific repressor of transcription, requires formation of complexes with specific HDACs. HDAC3, HDAC4, and HDAC9 have been found to be a corepressor of BCL6 (Lemercier et al., 2002; Pasqualucci et al., 2011; Gil et al., 2016). In the HDAC7 conditional deletion mice experiment, HDAC7 was deemed to control the pro-B cell to pre-B cell transition. In pro-B cells, the transcription factor ME2FC is complexed with HDAC7, which silences the lineage-inappropriate genes, ensuring the correct B cell differentiation (Barneda-Zahonero et al., 2015; Azagra et al., 2016). HDAC6 was also shown to be a controller of PD-L1 in B cells, regulating the immunogenicity (Powers et al., 2014). Selective HDAC6 inhibitors are considered to be a new target for immunotherapy, but the precise mechanism is needed for further investigation.

In the pathogenesis of lymphoma, HDAC-BCL6 complexes are often aberrant in the transcription step. For instance, the germinal centers (GC) of B cells in CREBBP-regulated/active enhancers are negatively regulated through H3K27 deacetylation by the BCL6-SMRT-HDAC3 complex. In folicullar lymphoma (FL) and diffuse large B cell lymphoma (DLBCL), however, CREBBP mutations lead to unopposed deacetylation by BCL6-SMRT-HDAC3 at an enhancer of B cell signal transduction and expression of immune response genes, which results in lymphomagenesis (Pasqualucci et al., 2011; Jiang et al., 2017). In B-NHL cells, the abnormal expression of HDAC9-BCL6 complex may cause B-lymphoproliferative disorders. Overexpression of HDAC9 contributes to alter pathways involved in growth and survival, as well as modulation of BCL6 activity and p53 tumor suppressor function (Gil et al., 2016). HDAC4 plays a key role in suppressing oncogenes. Dysfunction of HDAC4 disrupts the complex with BCL6 and this may lead to induce uncontrolled proliferation, clonogenic potential, and decreased apoptosis (Lemercier et al., 2002; Sandhu et al., 2012). Targeting these HDACs might therefore have promising effect in B cell lymphoma therapies.

Single agents of HDACIs has low response in all types of BCL. However, the significantly synergizing effect with other drugs makes it worth to be developed, especially selective HDAC inhibitors. Class I HDAC inhibitor improved the tolerability and reduced the toxicity and HDAC6 inhibitor also showed promising effect in combination with other drugs even overcome the drug resistance. These results may encourage us to fully understand the mechanism and develop more specific selective HDACIs.

Furthermore, fimepinostat, the first-in-class dual target inhibitor for DLBCL therapies, successfully decrease the toxicity comparing to dose single target agent. This may also give us an inspiration to develop other dual-target inhibitor.

One of the most curable cancer types, Hodgkin lymphoma (HL) is a type of B cell lymphoma, which has specific and unique characteristics. Hodgkin lymphoma was first been identified by Hodgkin in 1832 (Hodgkin, 1832). Subsequently, this lymphoma was named after him in 1865 by Wilks (Wilks, 1856). According to World Health organization (WHO), HL can be classified into two main types, classical Hodgkin lymphoma (cHL) and nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL). cHL accounts for 95% of all HL patients and the remainder are NLPHL. In this review we will mainly focus on cHL (Stathis and Younes, 2015).

In cHL patients, mononuclear Hodgkin cells and multinucleated Reed-Stemberg (HRS) cells arise from monoclonal B lymphocytes in the germinal center of lymphoid tissue and effect the rearrangement of IgG genes (Diehl, 2007). According to statistics, around 40% of cHL patients are infected by Epstein-Barr virus (EBV) and 100% of patients are infected with the human immunodeficiency virus (HIV). The apoptosis of these abnormal cells was inhibited in a manner which correlates with the expression of NF-κB, Notch 1 and some other transcription factors (Re et al., 2005). Research shows that, CD30 surface receptors, a member of tumor necrosis factor (TNF) receptor superfamily, will be characteristically expressed in HRS cells. The expression of TNF receptors mediates various signaling pathways, including the activation of NF-κB (Dürkop et al., 1992; Duckett et al., 1997).

To date, around 80% of cHL patients can be cured after receiving radiation therapy and chemotherapy. Recently, early and advanced stages in cHL patients were treated with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) in a first line and combined with bleomycin, etoposide, adriamycin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP) in a second line chemotherapy regimen. Although BEACOPP showed better overall survival rate than ABVD, its high acute toxicity makes ABVD more acceptable (Carde et al., 2016). Targeting CD30 on the other hand, is another strategy for cHL. In a combination with brentuximab vedotin and ABVD, it showed a promising therapeutic effect, but resulted in high pulmonary toxicity. By omitting bleomycin the toxicity was dramatically reduced, and this type of B-AVD therapy has become popular (Younes et al., 2013). For relapsed and refractory cHL patients, platinum- or gemcitabine-based therapies were used in a first line followed by autologous stem-cell transplantation, which can cure 60% of R/R cHL patients (Clavio et al., 2005). Nowadays, cHL is almost a curable disease, but delayed treatment-related toxicity may lead to second malignancies and cardiovascular disease (Armitage, 2010), and this has inspired a search for new therapeutic strategies.

As was mentioned previously, expression of abnormal HDACs has been found in both t cell and B cell lymphomas, which made it a promising therapeutic target. Because cHL is a type of B cell lymphoma, HDACs also are overexpressed in cHL. Research from Tzankov et al. shows that HDAC1, 2, and 3 are highly expressed in HRS cells. Interestingly, after treatment with HDACIs, the inhibition of HDAC1 inhibition in HRS cells leads to a poorer prognostic effect, for reasons that are still under investigation. Notwithstanding this, HDAC is still deemed a potent therapeutic target for cHL (Adams et al., 2010).

Recently, several HDACIs Figure 2 have been tested against R/R cHL in clinical trials, including panobinostat (Younes et al., 2012), vorinostat (NCT00132028), givinostat (NCT00496431), resminostat (NCT01037478), mocetinostat (NCT00358982), abexinostat (NCT00724984, NCT01149668), ricolinostat (NCT02091063), entinostat (NCT00866333), and tinostamustine (NCT02576496). These HDACIs were used as single treatment which brought patients positive results. Comparison, however, with other target therapies, such as PD-1 antibodies or some immunomodulatory antibodies, showed that HDACIs give relatively low overall response rates and comparable progression-free survivals (Adams et al., 2010). Above all, HDACIs might not be suitable for cHL treatment. On the other hand, HDACIs have been reported to have the ability to alter cytokines, which may enhance the immune response (Oki et al., 2014). Downregulation of PD1 on t cell and upregulation of OX40 ligand in HRS cells can exhibit antitumor immunity through HDAC11 inhibition (Buglio et al., 2011). This makes HDAC a favorable enhancer in numerous combination therapies and a number of clinical trials are now in progress. For instance, panobinostat has been used with everolimus (NCT00918333), lenalidomide (NCT01460940), cytarabine (NCT01321346), and ICE (NCT01169636). Other HDACIs are also being tested in combination therapies, such as combination of vorinostat with lenalidomide (NCT01116154), alisertib (NCT01567709), R-CHOP (NCT00667615), or a combination of mocetinostat with azacitidine (NCT00543582) and brentuximab vedotin (NCT02429375). Although some preliminary results showed high efficacy, further evaluation is necessary.

Similar to the role of HDACIs in BCL therapies, HDACIs are more like an enhancer in cHL therapies. It is certainly single dosage of HDACIs provided some positive result. However, other target therapies exhibited more potent in cHL therapies. In spite of that, HDACIs displayed dramatically increase of efficacy, when combined with other cHL therapies. Though, the clinical studies haven’t been completed yet, still give us some inspiration of HDACIs‘ character in cHL therapies.

As mentioned previously, HDACs play a crucial role in t cell regulation. In CD8 + t cells, the expression of PD1/PD-L1 has been shown through an inhibition assay by ACY241, a selective HDAC6 inhibitor to be positively controlled by HDAC6. Notably, HDACs other than HDAC6 are important in the CD8 + t cell immune response pathway (Yu et al., 2002; Adcock, 2007). Therefore, several HDACIs have been examined for their ability to reduce the tumor immunity (Bae et al., 2018).

Vorinostat and panobinostat have been used with immune cell stimulating antibodies in renal and colon carcinomas, and showed a surprising effect in inhibition of tumor growth (Christiansen et al., 2011). The selective HDAC inhibitor, entinostat, combined with IL-2 is also effective in a renal cell carcinoma mice model (Kato et al., 2007). Besides conventional HDAC inhibitors, some new compounds were synthesized for this kind of HDAC mediated immunotherapy (Vo et al., 2009). A novel HDAC and HSP90 dual inhibitor also causes downregulation of PD-L1 expression (Mehndiratta et al., 2020). These results are still in pre-clinical stages, but they provide a new aspect in immunotherapies.