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

J Clin Invest. 2020 May 1;130(5):2570-2586. doi: 10.1172/JCI133055.

Abstract

An in-depth understanding of immune escape mechanisms in cancer is likely to lead to innovative advances in immunotherapeutic strategies. However, much remains unknown regarding these mechanisms and how they impact immunotherapy resistance. Using several preclinical tumor models as well as clinical specimens, we identified a mechanism whereby CD8+ T cell activation in response to programmed cell death 1 (PD-1) blockade induced a programmed death ligand 1/NOD-, LRR-, and pyrin domain-containing protein 3 (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 antitumor 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 mechanism of adaptive resistance to anti-PD-1 checkpoint inhibitor immunotherapy and is a promising target for future translational research.

Keywords: Cancer immunotherapy; Chemokines; Immunology; Innate immunity; Oncology.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • B7-H1 Antigen / antagonists & inhibitors
  • B7-H1 Antigen / immunology*
  • CD8-Positive T-Lymphocytes / immunology
  • Cell Line, Tumor
  • Female
  • Humans
  • Immunotherapy
  • Inflammasomes / immunology*
  • Male
  • Melanoma / immunology
  • Melanoma / therapy*
  • Melanoma, Experimental / immunology
  • Melanoma, Experimental / therapy
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Models, Immunological
  • Myeloid-Derived Suppressor Cells / immunology
  • NLR Family, Pyrin Domain-Containing 3 Protein / antagonists & inhibitors
  • NLR Family, Pyrin Domain-Containing 3 Protein / genetics
  • NLR Family, Pyrin Domain-Containing 3 Protein / immunology*
  • Signal Transduction / immunology
  • Translational Medical Research
  • Tumor Escape / immunology
  • Tumor Microenvironment / immunology

Substances

  • B7-H1 Antigen
  • Inflammasomes
  • NLR Family, Pyrin Domain-Containing 3 Protein