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PPT1 inhibition enhances the antitumor activity of anti–PD-1 antibody in melanoma
Gaurav Sharma, … , Dmitry I. Gabrilovich, Ravi K. Amaravadi
Gaurav Sharma, … , Dmitry I. Gabrilovich, Ravi K. Amaravadi
Published August 11, 2020
Citation Information: JCI Insight. 2020;5(17):e133225. https://doi.org/10.1172/jci.insight.133225.
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Research Article Oncology Therapeutics

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

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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.

Authors

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

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Figure 6

PPT1 inhibition stimulates IFN-β secretion by macrophages via activation of cGAS/STING/TBK1 pathway and enhances T cell antitumor activity.

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PPT1 inhibition stimulates IFN-β secretion by macrophages via activation...
(A) Relative mass spectrometry signal of proteins in control, HCQ-treated, or DC661-treated MCM that showed a 5-fold increase and P < 0.05 in HCQ-treated MCM relative to control. (B) Dot plot representing ELISA performed for the measurement of IFN-β in HCQ- or DC661-treated MCM. Each result was obtained in duplicate, and the results were reproduced with 3 independent experiments. (C) Immunoblots showing cGAS, STING, and p-TBK1 protein status in macrophages treated with HCQ, DC661, or DMXAA for the time indicated. (D) Immunoblots for cGAS, STING, and p-TBK1 proteins in Ppt1-KD macrophages. (E) Dot plots representing ELISA performed for the measurement of IFN-β in HCQ- or DC661-treated or STING inhibitor C-176 or TBK1 inhibitor GSK-8612 cotreated MCM. Each result was obtained in duplicates, and the results were reproduced with 3 independent experiments. (F) Immunoblot showing the status of p-STAT1 in isotype or anti–IFN-β neutralizing Ab in the presence or absence of recombinant IFN-β in mouse splenocytes. (G) Percentage cytotoxicity elicited by primed splenocytes with exposure to MCM collected from RAW 264.7 macrophages treated with control, HCQ, or DC661 along with the administration of isotype or anti–IFN-β neutralizing Ab as indicated. Each result was obtained in duplicates, and the results were reproduced with 3 independent experiments. (H) Schematic showing the PPT1 inhibition results in reduced MDSCs tumor infiltrations and macrophage M2 to M1 switching. Polarized macrophages upon PPT1 inhibition secrete IFN-β, which enhances the CD8+ T cell–mediated tumor cell killing. One-way ANOVA and Dunnett’s procedure (B and E) or Tukey’s procedure (G).

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