Entinostat neutralizes myeloid-derived suppressor cells and enhances the antitumor effect of PD-1 inhibition in murine models of lung and renal cell carcinoma

Ashley Orillion, Ayumi Hashimoto, Nur Damayanti, Li Shen, Remi Adelaiye-Ogala, Sreevani Arisa, Sreenivasulu Chintala, Peter Ordentlich, Chingai Kao, Bennett Elzey, Dmitry Gabrilovich, Roberto Pili

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88 Scopus citations

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 (MMDSC) 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.

Original languageEnglish (US)
Pages (from-to)5187-5201
Number of pages15
JournalClinical Cancer Research
Volume23
Issue number17
DOIs
StatePublished - Sep 1 2017

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Orillion, A., Hashimoto, A., Damayanti, N., Shen, L., Adelaiye-Ogala, R., Arisa, S., Chintala, S., Ordentlich, P., Kao, C., Elzey, B., Gabrilovich, D., & Pili, R. (2017). Entinostat neutralizes myeloid-derived suppressor cells and enhances the antitumor effect of PD-1 inhibition in murine models of lung and renal cell carcinoma. Clinical Cancer Research, 23(17), 5187-5201. https://doi.org/10.1158/1078-0432.CCR-17-0741