Epigenetic, Metabolic, and Immune Crosstalk in Germinal-Center-Derived B-Cell Lymphomas: Unveiling New Vulnerabilities for Rational Combination Therapies

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.

Connections between metabolism and epigenetics: mechanisms and novel anti-cancer strategy

“…In summary, glutamine, acetyl-CoA acetyltransferase 1 (ATAC1), indoleamine 2,3-dioxygenase (IDO), lactate, and Toll-like receptors (TLRs) are likely to be considered as novel "metabolic checkpoints", targeting of which could assist immune cells to achieve better anti-tumor effect. Noteworthily, epigenetic, metabolism, and immune crosslink in germinal-cancer-derived B-cell lymphomas (GCB) uncover a rational triple combination therapy (Serganova et al, 2021). GCB lymphoma is significantly heterogenous based on genetic, epigenetic, and clinical characteristics.…”

Advances in Understanding of Metabolism of B-Cell Lymphoma: Implications for Therapy

“…While they all show efficacy and have been approved for low-grade lymphomas, their efficacy in DLBCL has generally been disappointing. They also show comparable toxicities to idelalisib, with copanlisib also having other serious side effects such as hyperglycemia and hypertension (reviewed in [ 88 ]).…”

“…A study of 120 DLBCL samples and 10 BL samples found that they all expressed MCT1 protein, but generally lacked expression of MCT4 [ 91 ]. A phase I expansion study of the MCT1 inhibitor AZD3965 in patients with relapsed/refractory DLBCL and BL has recently been reported [ 88 , 92 ]. Unfortunately, while the results of AZD3965 as a monotherapy were somewhat disappointing with only one out of eleven patients achieving a CR, this patient’s tumor did exhibit reduced FDG uptake as early as day 3 of therapy, consistent with the predicted impact of AZD3965 on glycolytic flux [ 92 ].…”

Primary extranodal diffuse large B‐cell lymphoma: Molecular features, treatment, and prognosis

“…Moreover, CREBBP and EP300 respectively encode CBP and p300 proteins, both of which possess histone acetyltransferase activity. Abnormal acetylation caused by CREBBP and EP300 variations inactivates p53 and the transcriptional repressor BCL6, favoring the lymphomagenesis 72–74 . Additionally, EZH2 is involved in the regulation of pathophysiological processes such as cell cycle, senescence, cell differentiation, and tumorigenesis by catalyzing the trimethylation of lysine at the 27th position of histone H3 (H3K27m3) and thereby inhibiting the expression of target genes 75 …”