TY - JOUR AU - Theivanthiran, Balamayoora AU - Evans, Kathy S. AU - DeVito, Nicholas C. AU - Plebanek, Michael AU - Sturdivant, Michael AU - Wachsmuth, Luke P. AU - Salama, April K.S. AU - Kang, Yubin AU - Hsu, David AU - Balko, Justin M. AU - Johnson, Douglas B. AU - Starr, Mark AU - Nixon, Andrew B. AU - Holtzhausen, Alisha AU - Hanks, Brent A. T1 - A tumor-intrinsic PD-L1/NLRP3 inflammasome signaling pathway drives resistance to anti–PD-1 immunotherapy PY - 2020/07/08/ AB - 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. JF - The Journal of Clinical Investigation JA - J Clin Invest SN - 0021-9738 DO - 10.1172/JCI133055 VL - 130 IS - 5 UR - https://doi.org/10.1172/JCI133055 SP - 2570 EP - 2586 PB - The American Society for Clinical Investigation ER -