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J Clin Invest. 2020 Feb 4. pii: 133055. doi: 10.1172/JCI133055. [Epub ahead of print]

A tumor-intrinsic PD-L1-NLRP3 inflammasome signaling pathway drives resistance to anti-PD-1 immunotherapy.

Author information

1
Division of Medical Oncology, Duke University, Durham, United States of America.
2
Division of Hematologic Malignancies and Cellular Therapy, Duke University, Durham, United States of America.
3
Department of Medicine, Vanderbilt University, Nashville, United States of America.
4
Department of Medicine, Vanderbilt School of Medicine, Nashville, United States of America.
5
Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, United States of America.
6
Department of Medicine / Pharmacology & Cancer Biology, Duke University, Durham, United States of America.

Abstract

An in-depth understanding of immune escape mechanisms in cancer are likely to lead to innovative advances in immunotherapeutic strategies. However, much remains unknown regarding these mechanisms and how they impact immunotherapy resistance. Using several pre-clinical tumor models as well as clinical specimens, we report a newly identified mechanism whereby CD8+ T cell activation in response to PD-1 blockade induced a PD-L1-NLRP3 inflammasome signaling cascade that ultimately led to the recruitment of granulocytic myeloid-derived suppressor cells (PMN-MDSCs) into tumor tissues, thereby dampening the resulting anti-tumor immune response. The genetic and pharmacologic inhibition of NLRP3 suppressed PMN-MDSC tumor infiltration and significantly augmented the efficacy of anti-PD-1 antibody immunotherapy. This pathway therefore represents a tumor-intrinsic adaptive resistance mechanism to anti-PD-1 checkpoint inhibitor immunotherapy and is a promising target for future translational research.

KEYWORDS:

Cancer immunotherapy; Chemokines; Immunology; Innate immunity; Oncology

PMID:
32017708
DOI:
10.1172/JCI133055
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