炎症体
免疫疗法
癌症免疫疗法
癌症研究
免疫系统
吡喃结构域
PD-L1
CD8型
程序性细胞死亡
信号转导
医学
细胞生物学
炎症
免疫学
生物
细胞凋亡
生物化学
作者
Balamayooran Theivanthiran,Kathy S. Evans,Nicholas C. DeVito,Michael P. Plebanek,Michael Sturdivant,Lucas P. Wachsmuth,April K.S. Salama,Yubin Kang,David S. Hsu,Justin M. Balko,Douglas B. Johnson,Mark D. Starr,Andrew B. Nixon,Alisha Holtzhausen,Brent A. Hanks
摘要
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.
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