A critical role for fas-mediated off-target tumor killing in t-cell immunotherapy

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Abstract

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.

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Upadhyay, R., Boiarsky, J. A., Pantsulaia, G., Svensson-Arvelund, J., Lin, M. J., Wroblewska, A., … Brody, J. D. (2021). A critical role for fas-mediated off-target tumor killing in t-cell immunotherapy. Cancer Discovery, 11(3), 599–613. https://doi.org/10.1158/2159-8290.CD-20-0756

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