Tumor Immune Microenvironment in Lymphoma: Focus on Epigenetics
Abstract
Lymphoma is a neoplasm arising from B or T lymphocytes or natural killer cells characterized by clonal lymphoproliferation. This tumor comprises a diverse and heterogeneous group of malignancies with distinct clinical, histopathological, and molecular characteristics. Despite advances in lymphoma treatment, clinical outcomes of patients with relapsed or refractory disease remain poor. Thus, a deeper understanding of molecular pathogenesis and tumor progression of lymphoma is required. Epigenetic alterations contribute to cancer initiation, progression, and drug resistance. In fact, over the past decade, dysregulation of epigenetic mechanisms has been identified in lymphomas, and the knowledge of the epigenetic aberrations has led to the emergence of the promising epigenetic therapy field in lymphoma tumors. However, epigenetic aberrations in lymphoma not only have been found in tumor cells, but also in cells from the tumor microenvironment, such as immune cells. Whereas the epigenetic dysregulation in lymphoma cells is being intensively investigated, there are limited studies regarding the epigenetic mechanisms that affect the functions of immune cells from the tumor microenvironment in lymphoma. Therefore, this review tries to provide a general overview of epigenetic alterations that affect both lymphoma cells and infiltrating immune cells within the tumor, as well as the epigenetic cross-talk between them.
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Citation: García-Domínguez, D.J.; Hontecillas-Prieto, L.; Palazón-Carrión, N.; Jiménez-Cortegana, C.; Sánchez-Margalet, V.; de la Cruz-Merino, L. Tumor Immune Microenvironment in Lymphoma: Focus on Epigenetics. Cancers 2022, 14, 1469. https://doi.org/10.3390/ cancers14061469 Academic Editor: David Wong Received: 31 January 2022 Accepted: 11 March 2022 Published: 13 March 2022 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Copyright: © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). cancers Review Tumor Immune Microenvironment in Lymphoma: Focus on Epigenetics Daniel J. García-Domínguez 1,2,*,† , Lourdes Hontecillas-Prieto 1,2,*,† , Natalia Palazón-Carrión2, Carlos Jiménez-Cortegana 1,2,3 , Víctor Sánchez-Margalet 1,‡ and Luis de la Cruz-Merino 2,‡ 1Clinical Laboratory, Department of Medical Biochemistry and Molecular Biology, School of Medicine, University of Seville, Virgen Macarena University Hospital, 41009 Seville, Spain; [email protected] (C.J.-C.); [email protected] (V.S.-M.) 2Oncology Service, Virgen Macarena University Hospital, Department of Medicines, School of Medicine, University of Seville, 41009 Seville, Spain; [email protected] (N.P.-C.); [email protected] (L.d.l.C.-M.) 3Department of Radiation Oncology, Weill Cornell Medical College, New York, NY 10065, USA *Correspondence: [email protected] (D.J.G.-D.); [email protected] (L.H.-P.) † These authors contributed equally to this work as first authors. ‡ These authors contributed equally to this work as senior authors. Simple Summary: Lymphoma and other cancers have been studied by mainly focusing on malignant cells. However, research findings about the role of the tumor microenvironment in the progression and immunosuppression of cancer, particularly in lymphomas, have increased considerably in recent years, allowing for a better understanding of the disease. Consequently, epigenetic mechanisms that are implicated in the interplay between tumor cells and the different components around them, promoting the survival and progression of the tumor, have been described. This review tries to summarize the complex interplay between lymphoma tumor cells and immune cells as well as the epigenetic alterations that result from this cross-talk, aiming at contributing towards underlining the value of epigenetic modifications as new biomarkers and the use of epigenetic drugs as an interesting therapeutic option. Abstract: Lymphoma is a neoplasm arising from B or T lymphocytes or natural killer cells characterized by clonal lymphoproliferation. This tumor comprises a diverse and heterogeneous group of malignancies with distinct clinical, histopathological, and molecular characteristics. Despite advances in lymphoma treatment, clinical outcomes of patients with relapsed or refractory disease remain poor. Thus, a deeper understanding of molecular pathogenesis and tumor progression of lymphoma is required. Epigenetic alterations contribute to cancer initiation, progression, and drug resistance. In fact, over the past decade, dysregulation of epigenetic mechanisms has been identified in lymphomas, and the knowledge of the epigenetic aberrations has led to the emergence of the promising epigenetic therapy field in lymphoma tumors. However, epigenetic aberrations in lymphoma not only have been found in tumor cells, but also in cells from the tumor microenvironment, such as immune cells. Whereas the epigenetic dysregulation in lymphoma cells is being intensively investigated, there are limited studies regarding the epigenetic mechanisms that affect the functions of immune cells from the tumor microenvironment in lymphoma. Therefore, this review tries to provide a general overview of epigenetic alterations that affect both lymphoma cells and infiltrating immune cells within the tumor, as well as the epigenetic cross-talk between them. Keywords: lymphoma; epigenetic; tumor microenvironment; immune cells Cancers 2022,14, 1469. https://doi.org/10.3390/cancers14061469 https://www.mdpi.com/journal/cancers
Cancers 2022,14, 1469 2 of 30 1. Introduction Cancer is a heterogeneous group of diseases that develop from normal cells. The successive abnormalities and changes in these normal cells drive their progressive transformation into malignant cells [1]. Although transformational events were traditionally associated with genetic changes [ 1 ], we currently know that cancer is caused by both genetic and epigenetic alterations. Each change provides advantageous properties to cancer cells, such as uncontrolled cell proliferation, resistance to cell death, evasion of apoptosis, invasiveness, and metastatic potential [ 2 , 3 ]. Thus, the interest in the epigenetic field has increased over the last decade in a wide variety of tumors. Given the importance of epigenetics in affecting cell function by providing disruptive properties, a better understanding of how epigenetic modifications regulate both tumor cells and the tumor microenvironment (TME) is mandatory. Tumors are a group of malignant cells that constantly interact with the TME, which contains different cell types, such as immune cells [ 4 ]. Lymphoma cells have been described to interact with the microenvironment to promote immune evasion [ 5 ]. In fact, the reciprocal interaction between lymphoma cells and immune cells (such as T and B cells) plays a key role in cancer initiation and progression [ 6 , 7 ]. In addition, immune cell function in the TME is affected by epigenetic alterations, which contributes to a favorable environment for tumor growth. As a result, tumor cells control immune cell functions through complex signaling networks, in which epigenetics plays an essential role. Summarizing, the epigenetic cross-talk between tumor cells and immune cells promotes tumor growth and immune escape of malignant cells [ 8 , 9 ], as well as a deficient response to therapy [ 10 ] both in solid and hematological cancers, including (but not limited to) lymphomas. Therefore, the underlying epigenetic mechanisms that govern both tumor and immune cells can be used as a strategy to disrupt this interaction and contribute to developing therapeutic strategies against cancer. 2. Lymphoma: An Overview Lymphoma represents a diverse and heterogeneous group of tumors and is among the ten most prevalent types of cancers worldwide [ 11 ]. This neoplasm arises from a clonal proliferation of lymphocytes. Specifically, lymphoma arises from B cell, T cell, or natural killer (NK) cell subsets at different stages of maturation [12,13]. Due to the diversity of lymphoid tumors, the first international classification of lymphoma malignancies was published in 2001 by the World Health Organization (WHO) [ 14 ]. Then, the classification was updated in 2008 and 2017 [ 14 ] to include important advances that had an impact on the diagnostic approach as well as on new therapeutic strategies for lymphoid neoplasms. The latest revision recognized more than 80 lymphoma subtypes classified into three main categories: B cell, T cell and NK cell neoplasms, and Hodgkin lymphomas. However, lymphomas have traditionally been classified as: (1) Hodgkin lymphoma (HL), which is characterized by the presence of Reed–Sternberg cells and accounts for 10–15% of cases, and (2) Non-Hodgkin lymphoma (NHL), which includes B cell NHLs, T cell NHLs (T NHLs), and natural killer (NK)/-cell NHLs and accounts for 80–85% of cases. Establishing the lymphoma diagnosis is essential to evaluate the clinical and histopathological features with molecular and immunologic studies [ 14 ], which, altogether, will provide better knowledge about both the severity and prognosis of the disease. Thus, for therapeutic purposes, the general practice is to treat lymphoma patients based on limited/indolent (low grade) or advanced/aggressive (high grade) disease [ 15 ]. Although indolent lymphomas have favorable prognoses, they are not usually curable at advanced stages. For this reason, relapsed and/or refractory patients have poor prognosis. There are multiple approved chemotherapy schedules in lymphoproliferative syndromes. Their use will depend mainly on the type of lymphoma, stage, disease situation (previously untreated or relapsed/refractory lymphoma), and characteristics of the patient (medically fit/unfit, comorbidities, age).
Cancers 2022,14, 1469 3 of 30 For untreated diffuse large B cell lymphoma (DLBCL), the most used schedule includes systemic chemotherapy (doxorubicin, cyclophosphamide, vincristine, and prednisone) plus immunotherapy with the recombinant anti-CD20 antibody rituximab (R-CHOP-21) given every 21 days, with estimated rates of progression-free survival (PFS) and overall survival (OS) of 70% and 75% for the advanced stage and rates of PFS and OS of 90% and 95% for the limited stage [ 16 , 17 ]. Although other chemoimmunotherapy regimens and schedules (dose-dense R-CHOP-14 or ACVBP—doxorubicin, cyclophosphamide, vindesine, bleomycin, prednisone followed by consolidation with methotrexate, etoposide, ifosfamide, cytarabine) have been used to treat DLBCL, none has a more favorable balance of outcomes and toxicity than R-CHOP [ 18 , 19 ]. For patients with advanced stage double-triple hit DLBCL (lymphomas with rearrangements of MYC and BCL2 and/or BCL6), acceptable intensive chemotherapy regimens include: dose-adjusted etoposide, doxorubicin, vincristine, cyclophosphamide, and prednisone plus rituximab (da-EPOCH-R), rituximab plus hyperfractionated cyclophosphamide, vincristine, doxorubicin and dexamethasone alternating with methotrexate and cytarabine (R-HyperCVAD/MA), rituximab plus cyclophosphamide, vincristine, doxorubicin, and high-dose methotrexate alternating with ifosfamide, etoposide, and cytarabine (R-CODOX-M/IVAC) given the worse prognosis of these patients. When compared with R-CHOP, more intensive front-line therapy (da-EPOCH-R, R-HyperCVAD/MA, R-CODOX-M/IVAC) was associated with superior three-year PFS (88 vs. 56%) [ 20 ]. Salvage chemotherapy (R-GDP, rituximab, gemcitabine, dexamethasone; R-ICE, rituximab, ifosfamide, carboplatin; R-DHAP, rituximab, dexamethasone, high dose cytarabine, cisplatin; R-GEMOX, rituximab, gemcitabine, oxaliplatin) followed by autologous hematopoietic cell transplantation (HCT) has long been the standard care in medically-fit patients with relapsed/refractory DLBCL (R/R DLBCL). It is associated with long-term survival in approximately half of patients with first relapse of DLBCL, and achieves superior OS (53 vs. 32%), overall response rate (ORR) (84 vs. 44%), and PFS (46 vs. 12%) compared with salvage therapy alone [ 21 ]. For patients unsuitable for autologous HCT, salvage treatments with rituximab combined with chemotherapy have a median OS and PFS of 10 and 6 months, respectively [ 22 ]. Other regimens in R/R DLBCL include polatuzumab–rituximab–bendamustine (median OS and PFS of 12 and 9 months) [ 23 ], tafasitamab–lenalidomide (median OS and PFS of 33 and 11 months) [ 24 ], and CAR T-cell therapies (ORR of 50–85% and CR of 47%) [25,26]. A treatment option for follicular, indolent, or mantle cell lymphoma is bendamustine plus rituximab (BR). Trials suggest similar efficacy and fewer side effects when compared with R-CHOP (median PFS 69.5 vs. 31.2 months; no difference in OS). ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine), the standard initial chemotherapy for patients with Hodgkin lymphoma (HL), shows OS rates at 5 and 10 years of approximately 85% and 55%, respectively, and CR rate of 80% in advanced stage [27]. Bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP) and variants of BEACOPP have shown advantages in FPS (85% with BEACOPP and 73% with ABVD, p= 0.004), but not OS (89% vs. 84%, respectively, p= 0.39), when compared with ABVD in several randomized trials in HL; additionally, severe adverse events occur more frequently in the BEACOPP than in the ABVD schedule [ 28 , 29 ]. Short-term outcomes with BV + AVD (brentuximab vedotin, an anti-CD30 antibody-drug conjugate, doxorubicin, vinblastine, and dacarbazine) are at least as favorable as ABVD, but cause less pulmonary toxicity, so this treatment is an acceptable alternative to ABVD for patients at higher risk for pulmonary toxicity and HL [ 30 ]. Patients with relapse/refractory HL (R/R HL) are generally treated with targeted chemotherapy BV plus bendamustine or intensive combination chemotherapy (ICE, DHAP, or gemcitabinecontaining regimens) and, if a response is demonstrated, start of autologous HCT, if eligible, with results in PFS rates from 30% to 50% [31]. Chemotherapy has improved the outcomes of lymphoma patients over the immunophenotypic subgroups and is the standard treatment for those patients, together with other treatments such as radiation, stem cell transplantation, targeted therapies, or immunother-
Cancers 2022,14, 1469 4 of 30 apies [ 32 – 34 ]. Immunotherapy has become a tool for lymphoma treatment as it restores the anti-tumor response of the patient’s immune system. It is described that Programmed Death 1 (PD-1) ligands, PD-L1 and PD-L2, are overexpressed by Hodgkin Reed–Sternberg (HRS) cells in classic HL (cHL), leading to evasion of immune surveillance. Therefore, anti-PD-1 antibodies such as nivolumab and pembrolizumab are used in lymphoma patients. Prospective phase II studies have reported high response rates with nivolumab and pembrolizumab in R/R cHL, but further study is required to establish the durability of treatment [ 35 – 37 ]. Nivolumab is approved for patients with cHL who relapsed or progressed after autologous HCT and post-transplantation brentuximab vedotin. Nivolumab showed 69% OR, including 16% CR and median PFS of 15 months [ 35 ]. Pembrolizumab is approved in the United States for patients whose disease is refractory or has relapsed after two or more lines of therapy and in the European Union for patients with progression after autologous HCT and brentuximab vedotin, or who are transplant-ineligible and have failed brentuximab vedotin. Pembrolizumab reported 72% OR, including 28% CR, and 14-month median PFS in heavily pretreated patients with r/r HL [36,37]. Although all these treatments have improved the outcomes of lymphoma patients, it is important to develop and identify novel strategies and therapies that could reduce drug resistance and increase the survival rate by minimizing adverse events. In fact, preclinical data and clinical trials are showing epigenetic agents as promising and potential therapeutic tools. 3. Tumor Microenvironment: Interaction of Immune and Lymphoma Tumor Cells Malignant cells need a dynamic and mutual communication with the components around the tumor to evade immune responses and progress. These components are a heterogeneous mix of immune cells, stromal cells, blood and lymphatic vessels, secreted factors, and extracellular matrix [ 38 , 39 ] which shape the TME. Thus, this interaction plays a pivotal role in supporting the survival and growth of the tumor, the invasion and metastasis, as well as the drug resistance and immune evasion [ 40 , 41 ]. As a result, the composition of the TME has been described to vary according to different cancer types and can predict the patients’ outcome in many cancers, including lymphomas [ 42 ]. For example, the TME constitutes more than 80% of the tumor mass in HL and several T-cell lymphoma subtypes, whereas it constitutes approximately 50% in indolent B-cell lymphomas or it is lower in aggressive lymphomas, DLBCL [42]. Immune cells are able to infiltrate tumors by promoting both pro- and anti-tumorigenic functions (Table 1). This dual relationship between immune cells and tumor cells depends on the context. Therefore, macrophages, dendritic cells (DCs), eosinophils, or tumorinfiltrated lymphocytes (TILs; T cells, B cells, and NK cells) have been demonstrated to be relevant for tumor control [ 43 ], whereas myeloid-derived suppressor cells (MDSCs), mast cells (MCs), regulatory T cells (Tregs), and type 2-polarized tumor-associated macrophages (TAMs) are important in immunosuppressing action [44]. Given the role of the immune cells in the behavior of the tumor, a deeper knowledge of interactions between them would be relevant to better understand the pathogenesis and prognosis of lymphomas as well as new therapeutic targets. For this reason, the interactions between lymphoma cells and surrounding immune cells are now being studied in much more detail. This section describes the interactions between lymphoma cells and some immune cells of the TME. Lymphoid cells: Lymphoid cells or lymphocytes are a type of white blood cell that develops from lymphoid progenitor cells that include T cells, B cells, and NK cells. These three types of lymphocytes are commonly found in the TME in lymphomas. (a) T cells are essential for both immune surveillance and disease progression. Therefore, they are being extensively studied in all types of cancers, including lymphoma subtypes [ 45 , 46 ]. The T cell compartment includes a variety of cell subpopulations with different immune functions: CD4+ T-helper cells (Ths), CD4+/FOXP3+ Tregs, and CD8+ cytotoxic T cells (CTLs). Additionally, there are two types of Th cells, which are Th1 and Th2
Cancers 2022,14, 1469 5 of 30 cells. Th1 cells produce interleukin (IL)-2, gamma-interferon (IFN- γ ) and tumor necrosis factor-beta (TNF-beta), activating CTLs, antigen-presenting cells (APCs), and NK cells [ 47 ]. In the meantime, Th2 cells express IL-4, IL-5, IL-6, and IL-10 and support tumor cell growth through CD40–CD40 ligand (CD40L) interactions in HL and Helicobacter-induced MALT lymphomagenesis [ 6 , 48 ]. Accordingly, lymphoma tumor cells can increase IL-10 secretion to produce CD40L by T cells [ 49 ]. In fact, IL-10RA or IL-10RB gene amplifications are described in DLBCL, promoting the tumor’s survival [ 50 , 51 ]. In follicular lymphoma (FL), Th cells are predominant and secrete IL-2, IL-4, IFN-γ, and CD40L [52]. It has been described that T cells surround but do not destroy tumor cells in vitro in HL, probably because T cells are less responsive and are attenuated in this disease [ 53 ]. In line with this notion, lymphoma tumor cells induce the expression of programmed cell PD-L1, and both CD4+ and CD8+ T-cells express PD-1, thus, the PD-1/PD-L1/2 interaction could suppress the activity of T cells and promote their exhaustion [ 54 ]. As a consequence, lymphoma tumor cells drive T cells to apoptosis or promote their differentiation towards Th2 via PD-L1 expression [ 55 ], which also enables an immunosuppressive environment in HL through the interaction with PD-1 from macrophages [56]. Tregs are abundant in B-cell NHL, such as FL or DLBCL, showing an immunosuppressive capacity [ 57 , 58 ]. However, the relevance of tumor infiltrating Tregs on disease outcome is unclear. In FL, FOXP3-positive Tregs have been considered as a negative prognostic factor [ 59 ], either alone or in cooperation with M2 macrophages from the TME. Nevertheless, FOXP3+ Tregs have also been associated with better outcomes in HL and other lymphoma subtypes [ 60 ], despite the high PD-1+ T cells [ 61 ] and CD68+ macrophages [ 62 ] that have been found. In DLBCL, high levels of Tim-3+Foxp3+Tregs within the TME have been considered as a prognostic factor for poor survival [ 58 ], whereas the high intratumor infiltration of CD25+FOXP3+ Tregs was correlated with a favorable prognosis in a meta-analysis [63]. Given the controversy in the role of different Treg subtypes in the prognosis and their capacity to express co-inhibitory and co-stimulatory markers, a recent study performed an in-depth characterization of Treg heterogeneity in NHL. Three different Treg subsets have been identified up to now, revealing the heterogeneity within the Treg compartment. The first one displayed a low expression of PD-1, OX40, and CTLA-4 that corresponded to peripheral blood Tregs. The second subset had high levels of PD-1, OX40, ICOS, TIGIT, CTLA-4 and CD28, CD69, and CD95/Fas (activation markers), and the third subset had a lack of FOXP3 and a high expression of LAG3, CTLA-4, IL-10, CD38, and KLRB1 (immunosuppression-associated genes) [57]. CD8+ cytotoxic T cells (CTLs) play an important role in infectious and malignant diseases. Thus, the anti-tumor effect of CTLs can be reversed depending on the type of lymphoma [ 64 , 65 ]. In this sense, the progression of Epstein–Barr virus (EBV)+ HL [ 66 ] or B-cell NHL [ 67 ] is suppressed by CTLs, whereas CTLs have also been associated with progression of CD8+ lymphomas, such as nodal cytotoxic T-cell lymphoma and cutaneous T-cell lymphoma (CTCL), towards their malignant transformation [68,69]. (b) B cells are the main humoral immune cells that play a role in antitumor immunity. In indolent lymphomas, non-malignant B cells are frequently encountered in the TME, but their role remains poorly understood [ 38 , 45 ]. Regarding their relationship with lymphoma tumor cells, normal and activated B cells from the germinal center express CD95 (also called FAS) to induce apoptosis. However, the loss of CD95 has been described in many lymphomas, including FL, MALT, and DLCBL [ 70 – 72 ]. Additionally, the expression of CD47 has been found in lower levels on normal B cells than in malignant B cells [ 73 ] in NHL, which could contribute to immune evasion. Finally, in mature B-cell lymphoma, B cells allow the progression of the disease inducing anergy in CD4+ T cells by CTLA-4 up-regulation [7]. (c) NK cells play a role in the response against infection and tumor cells, so the activation and detection of NK cells in the lymphoma tumor confer a favorable prognosis [ 74 ]. Due to the antitumor function of NK cells, lymphomas contribute to the quantitative and
Cancers 2022,14, 1469 6 of 30 functional deficiency of NK cells, which prevents tumor elimination [ 75 ]. Regardless of the HL subtype, the concentration of NK cells could be five times lower in affected tissues in comparison with normal tissues [ 75 ]. Moreover, a lower number of tumor infiltrating NK cells in HL was associated with poor prognosis and advanced clinical stages [ 76 ]. Many factors have been described to contribute in this reduction, such as IL-2 inhibition or the interruption of NKp30 and NKG2D surface receptors [ 77 ]. Indeed, a weak HL-derived NK cells cytolysis against the L428 HL cell line was observed by Reiners et al., in contrast to healthy donors where NK cells were able to efficiently eliminate lymphoma tumor cells [ 77 ]. This functional deficiency may be related to the significant reduction in NKG2D in NK cells of HL patients (p= 0.0001 for healthy versus untreated patients with HL) [77]. Tumor-associated macrophages (TAMs): Macrophages act against infection and injury via phagocytosis [ 78 ]. Due to their relevant role in TME, these cells are called TAMs, which have two different phenotypes depending on their activation states during tumor progression: M1 macrophages, which have anti-tumor effects because of their cytotoxic actions; and M2 macrophages, which promote tumor activity and support tumor growth [ 79 ]. The polarization towards M1 or M2 is influenced by cytokines secreted from both Th1 and Th2 cells, respectively [80]. Specifically in lymphomas, malignant cells were described to be able to induce macrophages to their M2 phenotype in vitro [ 81 ], which were associated with poor outcomes [ 82 , 83 ]. Although macrophages have been traditionally characterized by the expression of CD68 (a pan-macrophage marker that recognizes epitopes in a wide variety of tissue macrophages), several studies have revealed that M2 macrophages also express CD163 [ 84 ]. Accordingly, CD163+ TAMs have been associated with poor prognosis in many types of cancer, including lymphomas [ 85 , 86 ]. In DLBCL, a high number of CD68+/CD163+ or CD163+ M2 at diagnosis was significantly correlated with unfavorable prognosis [87,88]. In addition to CD68 and CD163 markers, it has also been described that MYC controls the expression of M2 specific genes, and its depletion in MYC+ macrophages inhibited tumor growth in melanoma and fibrosarcoma mouse models [ 89 ]. In line with this, a recent study evaluated the relevance of MYC-negative and -positive macrophages in HL patients based on positive CD68 and CD163 markers. The authors subdivided the patients into low, intermediate, and high groups based on the number of macrophages over the total number of CD68+ and CD163+ macrophages, the number of MYC+ macrophages, and the number of MYC − macrophages. The results showed that the worst outcomes were associated with a high number of CD163+/MYC+ cells, whereas the best outcomes were correlated with intermediate levels of CD68+/MYC+ macrophages [80]. Myeloid derived suppressor cells (MDSCs): MDSCs, originated from immature myeloid cells, are a group of heterogeneous cells characterized by suppressing immune responses [ 90 ]. Currently, MDSCs are generally defined by CD45+ CD3 − CD19 − CD20 − CD56 − CD16 − HLADR − CD33+ CD11b+ through flow cytometry [ 91 ]. Besides, there are two different subpopulations of MDSCs that can either express CD14 or CD15: monocytic MDSCs (M-MDSCs), which express CD14 and may differentiate into monocytes (such as macrophages and dendritic cells), and granulocytic MDSCs (G-MDSCs), which express CD15 and may differentiate into granulocytes (polymorphonuclear leukocytes) [ 90 – 92 ]. MDSCs mainly inhibit T cell immune responses by using different mechanisms, such as reactive oxygen species or nitrogen oxide production [ 93 ] and Tregs induction, which contributes to tumor dissemination [ 94 ]. Through the production of angiogenic factors and proteases, MDSCs also promote angiogenesis [ 95 ]. Additionally, MDSCs inhibit the maturation and functions of NK cells and induce the polarization of macrophages into their M2 phenotype by secreting IL-10 and transforming growth factor (TGF)-β[95,96]. Regarding the prognosis in lymphoma, the increased number of MDSCs has been correlated with a more aggressive disease in both HL and NHL [ 97 , 98 ]. Thus, MDSC expansion has been associated with tumor growth and the promotion of a immunosuppressed TME in HL [ 99 ]. Moreover, higher levels of MDSCs reduced the response rate in lymphoma patients [ 99 ]. Thus, MDSC count was increased compared with healthy controls (12.5% vs.
Cancers 2022,14, 1469 7 of 30 11%, respectively), but was higher in non-responders (19.7%) [ 99 ]. For this reason, several studies support the hypothesis that MDSCs may be promising prognostic biomarkers in lymphomas such as DLBCL [ 93 ], and, even more, the results also support their relevance as potential therapeutic targets to overcome immunosuppression [93]. Other studies have also evaluated the relevance of M-MDSCs and G-MDSCs in patients with lymphoma. In B-cell NHL and T-NHL patients, an accumulation of M-MDSCs was described in peripheral blood in comparison with healthy donors [ 100 – 102 ], which was correlated with poor survival and advanced lymphoma stage [ 100 , 102 , 103 ]. It was also noted that M-MDSCs returned to normal levels after clinical tumor remission and T cells were reestablished after removing M-MDSCs [ 101 , 102 , 104 , 105 ]. This result has also been described for G-MDSCs, wherein the median percentage of G-MDSCs was higher in patients with HL and B-NHL when compared to healthy donors (2.18 (0.02–70.92) vs. 0.42 (0.04–2.97), p< 0.0001). Considering HL, indolent, and aggressive B-cell NHL patients separately, the percentage of G-MDSCs was higher in the second group of patients (1.54 (0.28–26.34), (2.15 (0.02–20.08), and 2.96 (0.25–70.92), respectively, p< 0.0001) [ 98 ]. Moreover, high G-MDSC levels were found in the duodenum related to enteropathy-associated T cell lymphoma [106]. Table 1. Immune cells in tumor microenvironment of lymphoproliferative diseases. Immune Cells in TME Function Mechanism References Th1 cells Anti-tumor cells Produce IL-2, IFN-gamma, and TNF-beta. Activate CTLs, antigen-presenting cells (APCs), and NK cells [47] Th2 cells Pro-tumor cells Express IL-4, IL-5, IL-6, and IL-10 and support tumor cell growth through CD40–CD40L interactions [6,48] Tregs Pro- and anti-tumor cells Express co-inhibitory and co-stimulatory markers. Three different Treg subsets have been identified in NHL. High levels of PD-1, OX40, ICOS, TIGIT, CTLA-4 and CD28, CD69, and CD95/Fas (activation markers). The third subset of Tregs had a lack of FOXP3 and a high expression of LAG3 and CTLA-4, IL10, CD38, KLRB1 (immunosuppression-associated genes) [57] CTL cells Pro- and anti-tumor cells Suppression of the progression of B-cell NHL [42]. Induce the progression in nodal cytotoxic T-cell lymphoma and cutaneous T-cell lymphoma [43,44] [67–69] B cells Pro- and anti-tumor Contribute to immune evasion [48], B cells allowing the progression of the disease inducing anergy in CD4+ T cells by CTLA-4 up-regulation [49] [7,73] NK cells Anti-tumor cells IL-2 and NKp30 and NKG2D surface receptors [77] M2 macrophages Pro-tumor cells High number of CD163+/MYC+ cells in HL is associated with worst outcome [80] MDSCs Pro-tumor cells Inhibit T cell immune responses by reactive oxygen species or nitrogen oxide production. Inhibit the maturation and functions of NK cells and to induce macrophages polarization into M2 phenotype by secreting IL-10 and transforming growth factor (TGF)-βsecretion [93,95,96] 4. Epigenetic Epigenetic is a term introduced by developmental biologist Conrad Hal Waddington in 1942 in order to explain the dynamic interactions between the developmental environment and the genome [ 107 ]. Nowadays, epigenetic is generally accepted and defined as “the study of changes in gene function that are mitotically and/or meiotically heritable and that do not entail a change in DNA sequence” [ 108 ]. Epigenetics promotes changes in the chro-
Cancers 2022,14, 1469 8 of 30 matin structure, which regulates gene expression. These changes, unlike genetic changes, are reversible and comprise DNA methylation, histone modifications, and non-coding RNA [ 109 ]. Although the epigenetic role was first described as an essential mechanism for normal cell function, later, it was found that epigenetic disruptions promoted malignant cellular transformation leading to diverse human diseases, including cancer [ 110 – 112 ]. Pediatric tumors, such as Ewing sarcoma, are an example of the relevance of epigenetics in cancer. Indeed, pediatric tumors have been described to have a low frequency of somatic mutations together with hematological tumors [ 113 ]. The low frequency of mutations in these tumors does not explain the differences between those patients with different outcomes. Therefore, epigenetics constitutes a promising research area in order to understand the role of the epigenetic alterations in cancer and look for new alternatives to conventional strategies [114,115]. 4.1. Epigenetic Alterations in Lymphoma Increasing advances have allowed researchers to understand the relevance of epigenetic modifications, both in normal hematopoiesis and lymphoid development and in lymphoma. In fact, it has been described that changes in DNA methylation, histone modifications, and non-coding RNA are implicated in the development of B cells and in the maintenance of T-cell identity [ 116 – 118 ]. Moreover, it has been described that epigenetic alterations could be important to uncover the response to therapy and the prognosis in lymphoma malignancies [119,120] (Figure 1and Table 2). Cancers 2022, 14, x FOR PEER REVIEW 9 of 32 Figure 1. DNA methylation, non-coding RNA, and histone modifications as regulatory epigenetic mechanisms in lymphoma tumor cells. Table 2. Epigenetic modifications involved in lymphoma tumors. Epigenetic Subgroup Epigenetic Modifications/Mechanism Function DNA methylation DNMT1 overexpression: hipermethylation of tumor supressors promoters/impaired T-cell infiltration in the TME Pro-tumor cells DNMT 3A mutation: hypomethylation and Notch1 pathway activation Anti-tumor cells (mutation protumor cells) DNMT 3B overexpression: hipermethylation MYC promoter; downregulation: increases M2 macrophage expression markers (Arg1) Pro-tumor cells Histone acetylation HDAC1 overexpression: inhibits the tumor supressor BIM and increase in IL-15 secretion Pro-tumor cells HDAC2 and EZH2 overexpression: inhibits the tumor supressor BIM/mpaired T-cell infiltration in the TME Pro-tumor cells HDAC3 overexpression: downregulation: downregulation of inflammatory genes Pro-tumor cells (downregulation anti-tumor cells) HDAC6 overexpression: increase in IL-15 secretion Pro-tumor cells (PTCL ) and antitumor cells (DLBCL ) Figure 1. DNA methylation, non-coding RNA, and histone modifications as regulatory epigenetic mechanisms in lymphoma tumor cells.
Cancers 2022,14, 1469 9 of 30 Table 2. Epigenetic modifications involved in lymphoma tumors. Epigenetic Subgroup Epigenetic Modifications/Mechanism Function DNA methylation DNMT1 overexpression: hipermethylation of tumor supressors promoters/impaired T-cell infiltration in the TME Pro-tumor cells DNMT 3A mutation: hypomethylation and Notch1 pathway activation Anti-tumor cells (mutation pro-tumor cells) DNMT 3B overexpression: hipermethylation MYC promoter; downregulation: increases M2 macrophage expression markers (Arg1) Pro-tumor cells Histone acetylation HDAC1 overexpression: inhibits the tumor supressor BIM and increase in IL-15 secretion Pro-tumor cells HDAC2 and EZH2 overexpression: inhibits the tumor supressor BIM/mpaired T-cell infiltration in the TME Pro-tumor cells HDAC3 overexpression: downregulation: downregulation of inflammatory genes Pro-tumor cells (downregulation anti-tumor cells) HDAC6 overexpression: increase in IL-15 secretion Pro-tumor cells (PTCL) and anti-tumor cells (DLBCL) HDAC9 overexpression: modulates BCL6 activity and inhibits the tumor supressor p53; downregulation: downregulation of inflammatory genes Pro-tumor cells (downregulation pro-tumor cells) HDAC11: impaires immunosuppressive–MDSC capacity Anti-tumor cells Histone methylation EZH2 (catalyzes H3K27me3) overexpression: regulates MYC and induces high proliferation of/increases in NKG2D receptor Pro-tumor cells JMJD3 (promotes di- and tri-demethylation of H3K27) induces activation of Arg1, among other M2 markers Pro-tumor cells LSD1 (mono- or di-demethylase for H3K4) regulates infiltration of CD8+ T-cells into tumors Anti-tumor cells (downregulation pro-tumor cells) MLL2 (catalyzes H3K4 monomethyltransferase) mutation: alters genes expression (ARID1A, TRAF3) or signaling pathways (JAK-STAT or MAPK) Anti-tumor cells (mutation pro-tumor cells) SETD2 (catalyzes H3K36me3) mutation: enteropathy-associated T-cell lymphoma Anti-tumor cells (mutation pro-tumor cells) SMYD3 (catalyzes H3K4 and H4K5 methyltransferase) induces activation of Arg1, among other M2 markers Pro-tumor cells Non-coding RNA circ-APC regulates tumor cell proliferation Anti-tumor cells (downregulation pro-tumor cells) let-7 family inhibits MYC expression Anti-tumor cells miR-34b inhibits MYC expression Anti-tumor cells miR494 promotes the accumulation and activity of MDSCs by Akt pathway activation Pro-tumor cells miRNA-21 downregulation: increases PTEN expression and induces apoptosis Anti-tumor cells The most common epigenetic alterations in lymphoma are: DNA methylation: The process catalyzed by DNA methyltransferases (DNMTs), in which a methyl group is transferred to the C-5 position of the cytosine ring of DNA [ 121 ], is called DNA methylation. This epigenetic mechanism occurs within promoter regions where methylation regulates gene expression by transcription silencing [ 122 ]. The DNMT family is comprised of DNMT1, DNMT2, DNMT3A, DNMT3B, and DNMT3L members [123,124];
Cancers 2022,14, 1469 16 of 30 Table 3. Cont. NCT Number Title Conditions Phase NCT03141203 Evaluation of the Combination of Romidepsin and Carfilzomib in Relapsed/Refractory Peripheral T Cell Lymphoma Patients •Peripheral T-Cell Lymphoma •Phase 1 •Phase 2 NCT01796002 Efficacy and Safety of Romidepsin CHOP vs. CHOP inPatients with Untreated Peripheral T-Cell Lymphoma •Peripheral T-Cell Lymphoma Phase 3 NCT02616965 A Study to Assess the Feasibility of Romidepsin Combined with Brentuximab Vedotin in Cutaneous T-cell Lymphoma •Cutaneous T-Cell Lymphoma (CTCL) Phase 1 NCT01908777 A Phase 2 Multicenter Study of High Dose Chemotherapy with Autologous Stem Cell Transplant Followed by Maintenance Therapy with Romidepsin for the Treatment of T-Cell Non-Hodgkin Lymphoma •T-Cell Non-Hodgkin Lymphoma Phase 2 NCT01755975 Romidepsin in Combination with Lenalidomide in Adultswith Relapsed or Refractory Lymphomas and Myeloma •Multiple Myeloma •Non-Hodgkin’s Lymphoma •Phase 1 •Phase 2 NCT03534180 Venetoclax and Romidepsin in Treating Patients withRecurrent or Refractory Mature T-Cell Lymphoma •Anaplastic Large Cell Lymphoma •Recurrent Mature T-Cell and NK-Cell Non-Hodgkin Lymphoma •Refractory Mature T-Cell and NK-Cell Non-Hodgkin Lymphoma Phase 2 Belinostat (HDACi) NCT02737046 Belinostat Therapy With Zidovudine for Adult T-CellLeukemia-Lymphoma •Adult T-Cell Leukemia–Lymphoma •ATLL Phase 2 Panobinostat (HDACi) NCT01261247 Panobinostat in Treating Patients with Relapsed orRefractory Non-Hodgkin Lymphoma •Adult Nasal Type Extranodal NK/T-Cell Lymphoma •Anaplastic Large Cell Lymphoma •Angioimmunoblastic T-Cell Lymphoma • Extranodal Marginal Zone B-Cell Lymphoma of Mucosa-associated Lymphoid Tissue •Hepatosplenic T-Cell Lymphoma •Nodal Marginal Zone B-Cell Lymphoma •Peripheral T-Cell Lymphoma •Post-transplant Lymphoproliferative Disorder •Recurrent Adult Burkitt Lymphoma •Recurrent Adult Diffuse Large Cell Lymphoma Phase 2
Cancers 2022,14, 1469 17 of 30 Table 3. Cont. NCT Number Title Conditions Phase 5-azacytidine (DNMTi) NCT03450343 Oral Azacitidine Plus Salvage Chemotherapy inRelapsed/Refractory Diffuse Large B-Cell Lymphoma •Large B-Cell Diffuse Lymphoma Phase 1 NCT03703375 Efficacy and Safety of Oral Azacitidine (CC-486) Compared to Investigator’s Choice Therapy in Patients with Relapsed or Refractory Angioimmunoblastic T-Cell Lymphoma •Lymphoma, T-Cell Phase 3 NCT04897477 Azacytidine, Bendamustine, Piamprizumab inRefractory/Relapsed B-Cell Non-Hodgkin Lymphoma •Non-Hodgkin Lymphoma, B-Cell •Phase 1 •Phase 2 NCT04480125 Azacitidine Combined with Chidamide in the Treatment of Newly Diagnosed PTCL Unfit for Conventional Chemotherapy •Peripheral T-Cell Lymphoma Phase 2 NCT03593018 Efficacy and Safety of Oral Azacitidine Compared to Investigator’s Choice Therapy in Patients with Relapsed or Refractory AITL •Relapsed Angioimmunoblastic T-Cell •Lymphoma •Refractory Angioimmunoblastic T-Cell •Lymphoma Phase 3 NCT04747236 A Randomized, Phase IIB, Multicenter, Trial of Oral Azacytidine Plus Romidepsin Versus Investigator’s Choice in Patients with Relapse or Refractory Peripheral T-Cell Lymphoma (PTCL) •PTCL Phase 2 NCT05162976 CC-486 and Nivolumab for the Treatment of HodgkinLymphoma Refractory to PD-1 Therapy or Relapsed •Recurrent Classic Hodgkin Lymphoma •Refractory Classic Hodgkin Lymphoma Phase 1 NCT03542266 CC486-CHOP in Patients with Previously UntreatedPeripheral T-Cell Lymphoma •Previously Untreated Peripheral T-Cell Lymphoma Phase 2 NCT04578600 CC-486, Lenalidomide, and Obinutuzumab for the Treatment of Recurrent or Refractory CD20 Positive B- Cell Lymphoma •Indolent B-Cell Non-Hodgkin Lymphoma •Recurrent B-Cell Non-Hodgkin Lymphoma •Recurrent Chronic Lymphocytic Leukemia •Recurrent Mucosa-associated Lymphoid Tissue Lymphoma •Recurrent Follicular LymphomaRecurrent Hairy Cell Leukemia •Recurrent Lymphoplasmacytic Lymphoma •Recurrent Mantle Cell Lymphoma •Recurrent Marginal Zone Lymphoma •Refractory B-Cell Non-Hodgkin Lymphoma Phase 1
Cancers 2022,14, 1469 18 of 30 Table 3. Cont. NCT Number Title Conditions Phase NCT02828358 Azacitidine and Combination Chemotherapy in Treating Infants With Acute Lymphoblastic Leukemia and KMT2A Gene Rearrangement •Acute Leukemia of Ambiguous Lineage •B Acute Lymphoblastic Leukemia •Mixed Phenotype Acute Leukemia Phase 2 5-Aza-2-deoxycytidine (DNMTi) NCT02951728 Decitabine Plus R-CHOP in Diffuse Large B-CellLymphoma •Diffuse Large B-Cell Lymphoma •Phase 1 •Phase 2 NCT04697940 Decitabine-primed Tandem CD19/CD20 CAR T-Cells’Treatment in r/r B-NHL •Relapase and Refractory B-Cell Non- Hodgkin Lymphoma •Decitabine-primed Tandem CD19/CD20 CAR T Cells •Phase 1 •Phase 2 NCT04850560 Sequential Low-dose Decitabine with PD-1/CD28 CD19CAR-T in Relapsed or Refractory B-Cell Lymphoma •Objective Response Rate Phase 1 NCT03494296 A Prospective Study of Low-dose Decitabine Combined with COP Regimen in the Treatment of Relapsed and Refractory DLBCL •Lymphoma NCT04446130 Study of Decitabine Combined with HAAG Regimen in Newly Diagnosed ETP-ALL/LBL, T/M-MPAL, and ALL/ LBL with Myeloid or Stem Cell Markers Patients •Induction Chemotherapy •Acute T-Lymphocytic Leukemia •T-Cell Lymphoblastic Lymphoma Leukemia •T-Cell/Myeloid Mixed Phenotype Acute Leukemia Phase 3 NCT04553393 Decitabine-primed Tandem CD19/CD20 CAR T-Cells Plus Epigenetic Agents in Aggressive r/r B-NHL with Huge Tumor Burden •Refractory or Relapsed Aggressive r/r B- NHL With Huge Tumor Burden •Phase 1 •Phase 2
Cancers 2022,14, 1469 19 of 30 The previous results obtained in clinical trials have shown the effects of these epigenetic drugs in lymphoma patients. Azacitidine has been combined with chemotherapy and epigenetic drugs, among others. In a phase 1/2 trial (NCT01004991), the combination of azacitidine with R-CHOP reported a complete remission (CR) rate of 91.7% in untreated DLBCL patients. Moreover, the combination with vorinostat showed an ORR of 6.7% in patients with relapsed or refractory DLBCL in a phase 1/2 trial (NCT01120834). In B-NHL patients, decitabine decreased tumor DNMT1 and increased tumor apoptosis (p< 0.05), mitoses (p= 0.02), and copper/platinum transporter CTR1 [ 222 ]. Moreover, Blum et al. reported that the dose-limiting myelosuppression and infectious complications prevented dose escalation of decitabine to levels associated with changes in global methylation or gene re-expression in chronic lymphocytic leukaemia and NHL [223]. Regarding HDACis, vorinostat in monotherapy in a phase 1 trial conducted in FL, MCL, DLBL, and CTCL patients (NCT00127140) showed different responses in lymphoma patients, varying from CRs to worse responses [ 224 ]. A phase 2 trial (NCT00097929) testing vorinostat presented a CR of 5.6% in relapsed DLBCL. These studies with vorinostat in monotherapy seem to have a limited antitumor activity. However, vorinostat has sustained antitumor activity in patients with relapsed or refractory FL. In this phase 2 study, the ORR was 49% and the median PFS was 20 months for the 39 patients with FL [ 225 ]. In a combinatorial treatment, vorinostat plus rituximab in NHLs (phase 2 trial NCT00720876) showed an ORR of 50% in FL, 50% in MZL, 33% in MCL, and no response in LPL [ 226 ]. In a phase 1/2 study (NCT00972478), vorinostat combined with R-CHOP presented a tendency to improve R-CHOP efficacy in DLBCL (ORR 81% and CR 52%) [ 227 ]. Romidepsin or FK228 reported an ORR of 38% and CR 18% and an ORR of 34% and CR of 5.6% in relapsed or refractory PTCL and CTCL, respectively (phase 2 trial NCT00007345) [ 228 , 229 ]. Another HDACi, belinostat or PXD101, has shown an ORR of 10.5% (CR 0%) in relapsed or refractory aggressive B-NHLs (phase 2 trial NCT00303953) [ 230 ], and in another phase 2 trial (NCT00274651) involving relapsed or refractory PTCL or CTCL patients, belinostat presented an ORR of 25% (CR 8.3%) in PTCL and an ORR of 14% (CR 10.3%) in CTCL [ 231 ]. Finally, the combination of panobinostat and everolimus in relapsed HL and N-HL patients showed an ORR of 43% and CR of 15% [232]. With the clinical trial results, it might be argued that DNMT and HDAC inhibitors used as monotherapies seem to have limited efficacy in lymphoma in early phase studies. However, clinical trials that used combinatorial regimens have demonstrated potent efficacies in many lymphoma settings with an acceptable level of safety. Therefore, further research is essential to better know and understand the epigenetic mechanisms involved in the progression and prognosis in lymphomas, with the aim of developing new therapeutic approaches that significantly improve the clinical prognosis of patients. 5. Conclusions and Future Perspectives The role of epigenetic alterations in lymphoma and other tumors has been predominantly focused on tumor cells. However, compelling evidence also highlights the relevant role of the TME in supporting the proliferation, migration, and survival of lymphoma cells. For this reason, an increasing number of studies are describing the epigenetic modifications that appear in the TME cells and their role in creating an optimal immunosuppressive environment for tumor development. Nevertheless, a deeper understanding of the interrelationship between lymphoma tumor cells, TME, and the epigenetic mechanisms involved is essential. The extreme complexity of the interplay between the great variety of cells and the epigenetic alterations occurring in the context of the disease makes the challenge even greater. Nevertheless, a better understanding of this cross-talk would lead to advances in this field and would contribute to increasing our knowledge of the lymphoma disease. Accordingly, the epigenetic alterations could be used as new biomarkers in lymphoma, which would lead to patient stratification based on the expression of the epigenetic marks. Additionally, the use of epigenetic drugs might be an interesting therapeutic option [ 143 ]
Cancers 2022,14, 1469 20 of 30 in order to not only address the elimination of lymphoma tumor cells but also counteract the modulating effect of the heterogeneous components that shape the TME. Altogether, it would help to disrupt the dynamic and mutual communication between malignant and immune cells and, consequently, it would contribute to inhibiting tumor progression and chemoresistance or to modifying the immunosuppressive TME activity. Author Contributions: D.J.G.-D. and L.H.-P. conceived and wrote the manuscript and contributed to the figures’ design. N.P.-C., C.J.-C., V.S.-M. and L.d.l.C.-M. wrote the manuscript. All authors have read and agreed to the published version of the manuscript. Funding: This research received no external funding. Conflicts of Interest: The authors declare no conflict of interest. References 1. Hanahan, D.; Weinberg, R.A. Hallmarks of cancer: The next generation. Cell 2011,144, 646–674. [CrossRef] [PubMed] 2. Baylin, S.B.; Jones, P.A. 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