A tumor-intrinsic PD-L1/NLRP3 inflammasome signaling pathway drives resistance to anti-PD-1 immunotherapy.
Journal Article
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.
Full Text
Duke Authors
- DeVito, Nicholas Christian
- Hanks, Brent A.
- Kang, Yubin
- Nixon, Andrew Benjamin
- Salama, April Kelly Scott
Cited Authors
- Theivanthiran, B; Evans, KS; DeVito, NC; Plebanek, M; Sturdivant, M; Wachsmuth, LP; Salama, AK; Kang, Y; Hsu, D; Balko, JM; Johnson, DB; Starr, M; Nixon, AB; Holtzhausen, A; Hanks, BA
Published Date
- May 1, 2020
Published In
Volume / Issue
- 130 / 5
Start / End Page
- 2570 - 2586
PubMed ID
- 32017708
Pubmed Central ID
- 32017708
Electronic International Standard Serial Number (EISSN)
- 1558-8238
Digital Object Identifier (DOI)
- 10.1172/JCI133055
Language
- eng
Conference Location
- United States