HDAC inhibitor GCJ-490A modulates tumor microenvironment and synergizes with PD-1 antibody against breast and lung cancers in syngeneic murine models.

Abstract

Histone deacetylases (HDAC) inhibition represents one of the few validated strategies in epigenetic cancer therapies, demonstrating significant clinical efficacy in T-cell lymphomas and multiple myeloma, yet exhibiting limited efficacy against solid tumors. GCJ-490A is a novel HDAC inhibitor discovered by medicinal chemists in our institute, which exhibits potent in vitro and in vivo anticancer activity. In this study, we investigated the effects of GCJ-490A on the tumor microenvironment and its potential in synergy with PD-1 antibody in anti-tumor therapy. In syngeneic murine models of breast (EMT6) and lung (LL/2) cancers, we demonstrated that GCJ-490A alone and in combination with PD-1 antibody inhibited tumor growth by regulating T cells and tumor-associated macrophages (TAMs). Specifically, GCJ-490A significantly enhanced T-cell proliferation and cytotoxicity, evidenced by the increased expression of Ki67, CD107a and Granzyme B, and modulated TAMs towards a pro-inflammatory M1 phenotype, while reducing the M2 population. In addition, GCJ-490A upregulated PD-1 on T cells and PD-L1 on myeloid-derived suppressor cells (MDSCs) and TAMs, potentially enhancing PD-1 blockade efficacy. However, the anti-tumor efficacy was less pronounced in LL/2 tumors than in EMT6 tumors, which might be related to the increased infiltration of MDSCs in LL/2 tumors. GCJ-490A promoted MDSCs migration into the tumor by promoting the secretion of CXCL7 from LL/2 cells. In conclusion, GCJ-490A exerts its anti-tumor efficacy by reprogramming the tumor immune microenvironment in EMT6 and LL/2 tumor models, which is augmented when combined with anti-PD-1. However, CXCL7-mediated tumor-type-dependent recruitment of MDSCs by GCJ-490A may limit its therapeutic efficacy, and inhibition of the CXCL7/CXCR1/2 pathway might offer new strategies to address this challenge.