HDAC inhibitors overcome immunotherapy resistance in B-cell lymphoma

Abstract

Immunotherapy has been applied successfully to treat B-cell lymphomas in preclinical models or clinical settings. However, immunotherapy resistance is a major challenge for B-cell lymphoma treatment. To overcome this issue, combinatorial therapeutic strategies have been pursued to achieve a better efficacy for treating B-cell lymphomas. One of such strategies is to combine immunotherapy with histone deacetylase (HDAC) inhibitors. HDAC inhibitors can potentially increase tumor immunogenicity, promote anti-tumor immune responses, or reverse immunosuppressive tumor environments. Thus, the combination of HDAC inhibitors and immunotherapy has drawn much attention in current cancer treatment. However, not all HDAC inhibitors are created equal and their net effects are highly dependent on the specific inhibitors used and the HDACs they target. Hence, we suggest that optimal treatment efficacy requires personalized design and rational combination based on prognostic biomarkers and unique profiles of HDAC inhibitors. Here, we discuss the possible mechanisms by which B-cell lymphomas acquire immunotherapy resistance and the effects of HDAC inhibitors on tumor cells and immune cells that could help overcome immunotherapy resistance.

Metabolism of Amino Acids in Cancer

“…Histone acetylation can be regulated by acetyl-CoA from different sources in different cell conditions (Sivanand et al, 2018 ). HDACs, responsible for the removal of acetyl groups from histone lysine residues, have been reported to have abnormal expression in cancers, and HDAC inhibitors (HDACi) have been considered as potential drugs in cancer treatment (Audia and Campbell, 2016 ; Li and Seto, 2016 ; Peleg et al, 2016 ; San Jose-Eneriz et al, 2019 ; Mirzaei et al, 2020 ; Wang P. et al, 2020 ; Wang X. et al, 2020 ).…”

The Roles of Histone Deacetylases and Their Inhibitors in Cancer Therapy

“…Activation of the immune response by HDACi could also be an effective innate method to prevent cancer relapse when administered in a regimen with immunotherapeutic ( Guerriero et al, 2017 ; Wang X. et al, 2020 ). The class IIa HDACi TMP195 efficiently improves the durability of tumor reduction in breast cancer by strengthening the phagocytic role of macrophages that are involved in the IFNγ axis; it also activates the adaptive anti-tumor immune response.…”

Durable Response to Sintilimab and Chidamide in a Patient With Pegaspargase- and Immunotherapy-Resistant NK/T-Cell Lymphoma: Case Report and Literature Review

“…In addition to its direct anticancer activity, HDACi has pleiotropic immunomodulatory effects (31)(32)(33). HDACi can enhance the intratumoral infiltration of CD8+ T cells and macrophages, decrease the intratumoral infiltration of T-regulatory cells, myeloid-derived suppressor cells, and protumorigenic M2 macrophages, induce the intratumoral expression of multiple chemokines, upregulate the expression of MHC and co-stimulatory molecules, enhance immune recognition, promote tumor-specific T cell-mediated killing of cancer cells, and sensitize tumor cells to NK cell lysis (32,(34)(35)(36)(37)(38)(39)(40)(41)(42). Preclinical studies have demonstrated that HDACi can enhance the anticancer activity of immunotherapy in several types of cancers (36,37,(43)(44)(45).…”