PPT1 inhibition enhances the antitumor activity of anti-PD-1 antibody in melanoma.

Gaurav Sharma,David W Speicher,Ravi K Amaravadi,Michael C Nicastri,Rani Ojha,Sandra L Harper,Estela Noguera-Ortega,Xiaowei Xu,Shengfu Piao,Dmitry I Gabrilovich,Shujing Liu,Jennifer J Lee,John Attanasio,E John Wherry,Vito W Rebecca,Jeffrey D Winkler,Amruta Ronghe,Phyllis A Gimotty,Veena Jain ,Jérôme Mastio

doi:10.1172/jci.insight.133225

Abstract

New strategies are needed to enhance the efficacy of anti–programmed cell death protein antibody (anti–PD-1 Ab) in cancer. Here, we report that inhibiting palmitoyl-protein thioesterase 1 (PPT1), a target of chloroquine derivatives like hydroxychloroquine (HCQ), enhances the antitumor efficacy of anti–PD-1 Ab in melanoma. The combination resulted in tumor growth impairment and improved survival in mouse models. Genetic suppression of core autophagy genes, but not Ppt1, in cancer cells reduced priming and cytotoxic capacity of primed T cells. Exposure of antigen-primed T cells to macrophage-conditioned medium derived from macrophages treated with PPT1 inhibitors enhanced melanoma-specific killing. Genetic or chemical Ppt1 inhibition resulted in M2 to M1 phenotype switching in macrophages. The combination was associated with a reduction in myeloid-derived suppressor cells in the tumor. Ppt1 inhibition by HCQ, or DC661, induced cyclic GMP-AMP synthase/stimulator of interferon genes/TANK binding kinase 1 pathway activation and the secretion of interferon-β in macrophages, the latter being a key component for augmented T cell–mediated cytotoxicity. Genetic Ppt1 inhibition produced similar findings. These data provide the rationale for this combination in melanoma clinical trials and further investigation in other cancers.

Highlights

IntroductionWhile there have been extensive efforts to combine other T cell–stimulating factors with anti–programmed cell death protein antibody (anti–PD-1 Ab), there is an increasing interest in identifying T cell–independent strategies that will augment the efficacy of anti–PD-1 Ab
While there have been extensive efforts to combine other T cell–stimulating factors with anti–programmed cell death protein antibody, there is an increasing interest in identifying T cell–independent strategies that will augment the efficacy of anti–PD-1 Ab
Our findings show that palmitoyl-protein thioesterase 1 (PPT1) inhibition likely augments tumor immunity by at least 3 means: by causing an M2 to M1 macrophage polarization switch, by reducing the number of myeloid-derived suppressor cell (MDSC) in the tumor microenvironment, and by inducing IFN-β release from macrophages that stimulates T cell–mediated killing (Figure 6H)

Summary

Introduction

While there have been extensive efforts to combine other T cell–stimulating factors with anti–programmed cell death protein antibody (anti–PD-1 Ab), there is an increasing interest in identifying T cell–independent strategies that will augment the efficacy of anti–PD-1 Ab. Chloroquine and hydroxychloroquine (CQ and HCQ) are the only drugs that have been tested as autophagy inhibitors in clinical trials in patients with cancer. Multiple clinical trials involving HCQ in combination with chemotherapy or targeted therapy have demonstrated the safety of HCQ combination regimens and some preliminary antitumor activity in patients [5, 6]. We conducted preclinical studies with the clinically used PPT1 inhibitor HCQ in 2 immunocompetent mouse melanoma models and demonstrated an enhancement of tumor response when anti–PD-1 Ab was combined with HCQ. The combination of HCQ and anti–PD-1 Ab resulted in a change in TAM polarization and a significant reduction in myeloid-derived suppressor cell (MDSC) infiltration in vivo while each single agent did not.

Methods

Results

Conclusion