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, Chinghai Kao, Bennett Elzey, Dmitry Gabrilovich, Roberto Pili

Research output: Contribution to journalArticle

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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

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Renal Cell Carcinoma
Tumor Microenvironment
Lung
Immunosuppressive Agents
Neoplasms
Arginase
Histone Deacetylase Inhibitors
Survival
Growth
Myeloid-Derived Suppressor Cells
entinostat
Chemokines
Immunotherapy
Research Design
Cytokines
Therapeutics
Population

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Entinostat neutralizes myeloid-derived suppressor cells and enhances the antitumor effect of PD-1 inhibition in murine models of lung and renal cell carcinoma. / Orillion, Ashley; Hashimoto, Ayumi; Damayanti, Nur; Shen, Li; Adelaiye-Ogala, Remi; Arisa, Sreevani; Chintala, Sreenivasulu; Ordentlich, Peter; Kao, Chinghai; Elzey, Bennett; Gabrilovich, Dmitry; Pili, Roberto.

In: Clinical Cancer Research, Vol. 23, No. 17, 01.09.2017, p. 5187-5201.

Research output: Contribution to journalArticle

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, vol. 23, no. 17, pp. 5187-5201. https://doi.org/10.1158/1078-0432.CCR-17-0741
Orillion, Ashley ; Hashimoto, Ayumi ; Damayanti, Nur ; Shen, Li ; Adelaiye-Ogala, Remi ; Arisa, Sreevani ; Chintala, Sreenivasulu ; Ordentlich, Peter ; Kao, Chinghai ; Elzey, Bennett ; Gabrilovich, Dmitry ; Pili, Roberto. / Entinostat neutralizes myeloid-derived suppressor cells and enhances the antitumor effect of PD-1 inhibition in murine models of lung and renal cell carcinoma. In: Clinical Cancer Research. 2017 ; Vol. 23, No. 17. pp. 5187-5201.
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T1 - Entinostat neutralizes myeloid-derived suppressor cells and enhances the antitumor effect of PD-1 inhibition in murine models of lung and renal cell carcinoma

AU - Orillion, Ashley

AU - Hashimoto, Ayumi

AU - Damayanti, Nur

AU - Shen, Li

AU - Adelaiye-Ogala, Remi

AU - Arisa, Sreevani

AU - Chintala, Sreenivasulu

AU - Ordentlich, Peter

AU - Kao, Chinghai

AU - Elzey, Bennett

AU - Gabrilovich, Dmitry

AU - Pili, Roberto

PY - 2017/9/1

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N2 - 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.

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