J Cancer 2020; 11(14):4059-4072. doi:10.7150/jca.44622
HDAC Inhibitor, CG-745, Enhances the Anti-Cancer Effect of Anti-PD-1 Immune Checkpoint Inhibitor by Modulation of the Immune Microenvironment
Institute for Drug Discovery, CrystalGenomics, Inc., Korea Bio Park, 700 Daewangpangyo-ro, Bundang-gu, Seongnam-si, Gyeonggi-do 13488, Korea
*These authors provided equal contribution
Kim YD, Park SM, Ha HC, Lee AR, Won H, Cha H, Cho S, Cho JM. HDAC Inhibitor, CG-745, Enhances the Anti-Cancer Effect of Anti-PD-1 Immune Checkpoint Inhibitor by Modulation of the Immune Microenvironment. J Cancer 2020; 11(14):4059-4072. doi:10.7150/jca.44622. Available from http://www.jcancer.org/v11p4059.htm
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.
Keywords: CG-745, HDAC, PD-1, TME, Treg, MDSC, Hepatocellular carcinoma, Colorectal cancer