Abstract
B-cell non-Hodgkin lymphomas (B-NHLs) are highly heterogenous by genetic, phenotypic, and clinical appearance. Next-generation sequencing technologies and multi-dimensional data analyses have further refined the way these diseases can be more precisely classified by specific genomic, epigenomic, and transcriptomic characteristics. The molecular and genetic heterogeneity of B-NHLs may contribute to the poor outcome of some of these diseases, suggesting that more personalized precision-medicine approaches are needed for improved therapeutic efficacy. The germinal center (GC) B-cell like diffuse large B-cell lymphomas (GCB-DLBCLs) and follicular lymphomas (FLs) share specific epigenetic programs. These diseases often remain difficult to treat and surprisingly do not respond advanced immunotherapies, despite arising in secondary lymphoid organs at sites of antigen recognition. Epigenetic dysregulation is a hallmark of GCB-DLBCLs and FLs, with gain-of-function (GOF) mutations in the histone methyltransferase EZH2, loss-of-function (LOF) mutations in histone acetyl transferases CREBBP and EP300, and the histone methyltransferase KMT2D representing the most prevalent genetic lesions driving these diseases. These mutations have the common effect to disrupt the interactions between lymphoma cells and the immune microenvironment, via decreased antigen presentation and responsiveness to IFN-γ and CD40 signaling pathways. This indicates that immune evasion is a key step in GC B-cell lymphomagenesis. EZH2 inhibitors are now approved for the treatment of FL and selective HDAC3 inhibitors counteracting the effects of CREBBP LOF mutations are under development. These treatments can help restore the immune control of GCB lymphomas, and may represent optimal candidate agents for more effective combination with immunotherapies. Here, we review recent progress in understanding the impact of mutant chromatin modifiers on immune evasion in GCB lymphomas. We provide new insights on how the epigenetic program of these diseases may be regulated at the level of metabolism, discussing the role of metabolic intermediates as cofactors of epigenetic enzymes. In addition, lymphoma metabolic adaptation can negatively influence the immune microenvironment, further contributing to the development of immune cold tumors, poorly infiltrated by effector immune cells. Based on these findings, we discuss relevant candidate epigenetic/metabolic/immune targets for rational combination therapies to investigate as more effective precision-medicine approaches for GCB lymphomas.
Highlights
Despite the clinical success of immune checkpoint blockade (ICB) therapy in solid tumors (Zappasodi et al, 2018a; Zappasodi et al, 2018b; Ribas and Wolchok, 2018), B-cell lymphomas remain largely refractory to these treatments, with the exception of Hodgkin’s lymphoma, where PD-L1 constitutes a direct tumor target (Zappasodi et al, 2015; Ansell, 2019; Armand et al, 2021a)
Atezolizumab has been combined with R-CHOP in untreated diffuse large B-cell lymphomas (DLBCLs), with patients receiving atezolizumab consolidation following induction with atezo-RCHOP, with an Overall response rate (ORR) of 87.5% (77.5% complete response (CR)) and a 2-years progression-free survival (PFS) of 75%, half of the patients discontinued consolidation prior to completion and half had grade 3–4 adverse events during consolidation (Younes et al, 2019). These results indicate that PD-1/PD-L1 inhibitors have limited single-agent efficacy in GCB lymphomas, but there remains significant clinical potential when combined with other therapies, including epigenetic modulators and agents targeting tumor metabolism, as discussed below
The degree of heterogeneity and derangement from the epigenetic status and dynamics of normal B-cells correlate with disease severity and patient survival (Abramson et al, 2020), adding more complexity to the genetic basis of B-cell lymphomas, with more than 150 genetic driver mutations identified (Chapuy et al, 2018). 85% of all DLBCL cases demonstrate alterations in at least one gene involved in epigenetic remodeling (García-Ramírez et al, 2017; Zhang et al, 2017), such as the histone methyltransferase KMT2D (Kawalekar et al, 2016), EZH2 (Elpek et al, 2007), and the histone acetyltransferases (HATs) CREBBP and EP300 (Alam et al, 2020)
Summary
Despite the clinical success of immune checkpoint blockade (ICB) therapy in solid tumors (Zappasodi et al, 2018a; Zappasodi et al, 2018b; Ribas and Wolchok, 2018), B-cell lymphomas remain largely refractory to these treatments, with the exception of Hodgkin’s lymphoma, where PD-L1 (programmed deathligand 1) constitutes a direct tumor target (Zappasodi et al, 2015; Ansell, 2019; Armand et al, 2021a). Recent efforts to improve the genetic classification of diffuse large B-cell lymphomas (DLBCLs)—the most common lymphoid malignancy in adults (Swerdlow et al, 2016)—have revealed the effect of specific driver epigenetic mutations to alter expression of T-cell immune co-receptors and/or downstream signaling molecules (Chapuy et al, 2018; Wright et al, 2020). These genetic features occur more frequently in germinal center (GC) subtypes of DLBCL and are shared by follicular lymphoma (FL)—the second most frequent form of B-NHLs, which is of GC origin (Morin et al, 2010; Carbone et al, 2019) (abbreviated thereafter as GCB lymphomas). Mutational characteristics of GCB-DLBCL and FL are similar and mutations in epigenetic modifier genes may play essential roles for the development and progression of these diseases
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