HDAC Inhibitor, CG-745, Enhances the Anti-Cancer Effect of Anti-PD-1 Immune Checkpoint Inhibitor by Modulation of the Immune Microenvironment

Abstract

Histone deacetylase inhibitors (HDACis) are well-known epigenetic regulators with therapeutic potential in various diseases. Recent studies have shown that HDACis are involved in immune-mediated anti-cancer effects and may modulate the activity of immunotherapy agents. CG-745, a histone deacetylase inhibitor, has shown anti-cancer effects in pancreatic cancer, colorectal cancer, and non-small cell lung cancer. However, the exact role of CG-745 within the immune system is largely unknown. In this study, we have shown that CG-745 induces microenvironment changes promoting anti-cancer effect of anti-PD-1 antibody in syngeneic mouse models. Specifically, CG-745 induces or extends IL-2 and IFN-γ expression with or without additional stimulation, and increases proliferation of cytotoxic T cells and NK cells, while inhibiting proliferation of regulatory T cells. The analysis of immune cell distribution in the tumor microenvironment and spleen reveals that CG-745 suppresses M2 macrophage polarization and decreases the myeloid-derived suppressor cells. Recent advances in immunotherapy highlight the anti-cancer effects of immune checkpoint inhibitor despite a relatively limited clinical benefit in the subset of patients. Our results indicate that CG-745 enables the synergistic effects of the immune checkpoint inhibitor combination therapy in various cancers by suppressing tumor microenvironment.

Identification of HCG18 and MCM3AP-AS1 That Associate With Bone Metastasis, Poor Prognosis and Increased Abundance of M2 Macrophage Infiltration in Prostate Cancer

“…More importantly, HDAC inhibitor CG-745 was demonstrated to enhance the anti-cancer effect of anti-PD-1 antibody by changing the immune microenvironment, including increasing cytotoxic T cells and NK cells, while decreasing regulatory T cells and M2 macrophages. 68 Trichostatin A treatment made the HepG2 cells more susceptible to NK cell-mediated killing, 69 which may be accompanied by reduced M2 type macrophages. 60 In this study, HCG18 and MCM3AP-AS1 were identified to be associated with M2 type macrophages.…”

Anticancer Therapy with HDAC Inhibitors: Mechanism-Based Combination Strategies and Future Perspectives

“…Additionally, Treg depletion is considered as responsible for improved ICI results upon HDACi treatment [ 175 ]. TNBCs were cocultured with peripheral blood mononuclear cells.…”

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).…”