Entinostat Neutralizes Myeloid-Derived Suppressor Cells and Enhances the Antitumor Effect of PD-1 Inhibition in Murine Models of Lung and Renal Cell Carcinoma

Clin Cancer Res. 2017 Sep 1;23(17):5187-5201. doi: 10.1158/1078-0432.CCR-17-0741. Epub 2017 Jul 11.

Abstract

Purpose: Recent advances in immunotherapy highlight the antitumor effects of immune checkpoint inhibition despite a relatively limited subset of patients receiving clinical benefit. The selective class I histone deacetylase inhibitor entinostat has been reported to have immunomodulatory activity including targeting of immune suppressor cells in the tumor microenvironment. Thus, we decided to assess whether entinostat could enhance anti-PD-1 treatment and investigate those alterations in the immunosuppressive tumor microenvironment that contribute to the combined antitumor activity.

Experimental design: We utilized syngeneic mouse models of lung (LLC) and renal cell (RENCA) carcinoma and assessed immune correlates, tumor growth, and survival following treatment with entinostat (5 or 10 mg/kg, p.o.) and a PD-1 inhibitor (10 and 20 mg/kg, s.c.).

Results: Entinostat enhanced the antitumor effect of PD-1 inhibition in two syngeneic mouse tumor models by reducing tumor growth and increasing survival. Entinostat inhibited the immunosuppressive function of both polymorphonuclear (PMN)- and monocytic-myeloid derived suppressor cell (M-MDSC) populations. Analysis of MDSC response to entinostat revealed significantly reduced arginase-1, iNOS, and COX-2 levels, suggesting potential mechanisms for the altered function. We also observed significant alterations in cytokine/chemokine release in vivo with a shift toward a tumor-suppressive microenvironment.

Conclusions: Our results demonstrate that entinostat enhances the antitumor effect of PD-1 targeting through functional inhibition of MDSCs and a transition away from an immune-suppressive tumor microenvironment. These data provide a mechanistic rationale for the clinical testing and potential markers of response of this novel combination in solid tumor patients.

MeSH terms

  • Animals
  • Benzamides / administration & dosage
  • Carcinoma, Non-Small-Cell Lung / drug therapy*
  • Carcinoma, Non-Small-Cell Lung / genetics
  • Carcinoma, Non-Small-Cell Lung / immunology
  • Carcinoma, Non-Small-Cell Lung / pathology
  • Carcinoma, Renal Cell / drug therapy*
  • Carcinoma, Renal Cell / genetics
  • Carcinoma, Renal Cell / immunology
  • Carcinoma, Renal Cell / pathology
  • Disease Models, Animal
  • Histone Deacetylase Inhibitors / administration & dosage
  • Humans
  • Immune Tolerance / immunology
  • Immunotherapy / methods
  • Mice
  • Myeloid-Derived Suppressor Cells / immunology*
  • Programmed Cell Death 1 Receptor / antagonists & inhibitors*
  • Programmed Cell Death 1 Receptor / immunology
  • Pyridines / administration & dosage
  • Tumor Microenvironment / drug effects
  • Tumor Microenvironment / immunology

Substances

  • Benzamides
  • Histone Deacetylase Inhibitors
  • Pdcd1 protein, mouse
  • Programmed Cell Death 1 Receptor
  • Pyridines
  • entinostat