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

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 (HDACi) 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 anti-tumor 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 PMN- and 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 from an immunosuppressive to 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.

EGFR‐targeted therapy alters the tumor microenvironment in EGFR‐driven lung tumors: Implications for combination therapies

“…Prior research has demonstrated that MDSCs develop resistance to checkpoint inhibitors, and therapies that eliminate MDSCs have synergistic effects with PD‐1/PD‐L1 inhibitors . Our study showed that sensitive EGFR‐TKIs increase the infiltration of MDSCs, particularly M‐MDSCs.…”

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“…Interestingly, entinostat treatment in combination with anti-CTLA4 and anti-PD1 prevented development of metastatic lesions and was able to eradicate primary tumors (Kim et al, 2014). In that study, a reduction of PMN-MDSC was seen only in combination with checkpoint blockade, which may explain the opposing results from Kumar et al In a different study, also from the Gabrilovich group, the authors recently described that entinostat enhanced anti-tumor effects of PD-1 inhibition in mice (Orillion et al, 2017), supporting the study by Kim et al (Kim et al, 2014). However, in this case the authors provide data suggesting that PMN-MDSC and M-MDSC lost their immunosuppressive function upon entinostat treatment, even if entinostat alone may have caused an increase in PMNMDSC numbers (Orillion et al, 2017).…”

“…In that study, a reduction of PMN-MDSC was seen only in combination with checkpoint blockade, which may explain the opposing results from Kumar et al In a different study, also from the Gabrilovich group, the authors recently described that entinostat enhanced anti-tumor effects of PD-1 inhibition in mice (Orillion et al, 2017), supporting the study by Kim et al (Kim et al, 2014). However, in this case the authors provide data suggesting that PMN-MDSC and M-MDSC lost their immunosuppressive function upon entinostat treatment, even if entinostat alone may have caused an increase in PMNMDSC numbers (Orillion et al, 2017). One alternate explanation may be that entinostat has different effects on the frequency and function of MDSC when combined with immune checkpoint inhibitors.…”

“…A number of prior studies, including one from the Gabrilovich group (Kim et al, 2014; Orillion et al, 2017; Wang et al, 2017), have looked at histone deacetylase (HDAC) inhibitors and MDSC frequencies, function, and anti-tumor immunity. Entinostat is a class I HDAC inhibitor, which is currently in clinical evaluation as a single agent and in combination with immune checkpoint blockade inhibitors.…”

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“…Similarly, entinostat, a selective class I and class IV histone deacetylase inhibitor, has been shown to significantly reduce arginase-1, iNOS and COX-2 levels and to neutralize MDSCs. The combination of entinostat and PD-1 inhibition yielded enhanced antitumor effects in murine models of lung and renal cell carcinoma compared to PD-1 inhibition alone 164 .…”