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

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 were reproduced in chimeric antigen receptor (CAR-T) and bispecific antibody T cell models and were 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.

journal_name

Cancer Discov

journal_title

Cancer discovery

authors

Upadhyay R,Boiarsky JA,Pantsulaia G,Svensson-Arvelund J,Lin MJ,Wroblewska A,Bhalla S,Scholler N,Bot A,Rossi JM,Sadek N,Parekh S,Laganà A,Baccarini A,Merad M,Brown BD,Brody JD

doi

10.1158/2159-8290.CD-20-0756

subject

Has Abstract

pub_date

2020-12-17 00:00:00

eissn

2159-8274

issn

2159-8290

pii

2159-8290.CD-20-0756

pub_type

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