旁观者效应
抗原
癌症研究
免疫疗法
嵌合抗原受体
生物
T细胞
免疫系统
肿瘤抗原
体内
细胞毒性T细胞
细胞凋亡
Fas配体
免疫学
程序性细胞死亡
体外
生物技术
生物化学
作者
Ranjan Upadhyay,Jonathan Boiarsky,Gvantsa Pantsulaia,Judit Svensson-Arvelund,Matthew J. Lin,Aleksandra Wroblewska,Sherry Bhalla,Nathalie Scholler,Adrian Bot,John M. Rossi,Norah Sadek,Samir Parekh,Alessandro Laganà,Alessia Baccarini,Miriam Merad,Brian D. Brown,Joshua Brody
出处
期刊:Cancer Discovery
[American Association for Cancer Research]
日期:2021-03-01
卷期号:11 (3): 599-613
被引量:67
标识
DOI:10.1158/2159-8290.cd-20-0756
摘要
T cell-based therapies have induced cancer remissions, though most tumors ultimately progress, reflecting inherent or acquired resistance including antigen escape. Better understanding of how T cells eliminate tumors will help decipher resistance mechanisms. We used a CRISPR/Cas9 screen and identified a necessary role for Fas-FasL in antigen-specific T-cell killing. We also found that Fas-FasL mediated off-target "bystander" killing of antigen-negative tumor cells. This localized bystander cytotoxicity enhanced clearance of antigen-heterogeneous tumors in vivo, a finding that has not been shown previously. Fas-mediated on-target and bystander killing was reproduced in chimeric antigen receptor (CAR-T) and bispecific antibody T-cell models and was augmented by inhibiting regulators of Fas signaling. Tumoral FAS expression alone predicted survival of CAR-T-treated patients in a large clinical trial (NCT02348216). These data suggest strategies to prevent immune escape by targeting both the antigen expression of most tumor cells and the geography of antigen-loss variants. SIGNIFICANCE: This study demonstrates the first report of in vivo Fas-dependent bystander killing of antigen-negative tumors by T cells, a phenomenon that may be contributing to the high response rates of antigen-directed immunotherapies despite tumoral heterogeneity. Small molecules that target the Fas pathway may potentiate this mechanism to prevent cancer relapse.This article is highlighted in the In This Issue feature, p. 521.
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