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

摘要: Purpose: Recent advances in immunotherapy highlight the antitumor effects of immune- checkpoint inhibition despite a relatively limited subset patients receiving clinical benefit. The selective class I histone deacetylase inhibitor (HDACi) entinostat has been reported to have immunomodulatory activity including targeting immune suppressor cells tumor microenvironment. Thus, we decided assess whether could enhance anti-PD-1 treatment and investigate those alterations immunosuppressive microenvironment that contribute combined anti-tumor activity. Experimental design: We utilized syngeneic mouse models lung (LLC) renal cell (RENCA) carcinoma, assessed correlates, growth survival following with (5 or 10 mg/kg, P.O.) PD-1 (10 20 s.c.). Results: Entinostat enhanced effect two by reducing increasing survival. inhibited function both PMN- M-MDSC populations. Analysis MDSC response revealed significantly reduced arginase-1, iNOS COX-2 levels, suggesting potential mechanisms for altered function. also observed significant cytokine/chemokine release vivo shift towards suppressive Conclusions: Our results demonstrate enhances through functional MDSCs, transition away from an These data provide mechanistic rationale testing markers this novel combination solid patients.