A critical role for fas-mediated off-target tumor killing in T cell immunotherapy
Autor: | Aleksandra Wroblewska, Jonathan A. Boiarsky, Brian D. Brown, Matthew J Lin, John M. Rossi, Miriam Merad, Sherry Bhalla, Nathalie Scholler, Gvantsa Pantsulaia, Adrian Bot, Judit Svensson-Arvelund, Joshua Brody, Alessandro Laganà, Alessia Baccarini, Samir Parekh, Ranjan Upadhyay, Norah Sadek |
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Jazyk: | angličtina |
Rok vydání: | 2020 |
Předmět: |
0301 basic medicine
Cytotoxicity Immunologic T cell T-Lymphocytes T-Cell Antigen Receptor Specificity Biology CD8-Positive T-Lymphocytes Immunotherapy Adoptive Article 03 medical and health sciences Mice 0302 clinical medicine Antigen In vivo Antigens Neoplasm Neoplasms medicine Bystander effect CRISPR Animals Humans fas Receptor Cytotoxicity Gene Editing Mice Knockout Receptors Chimeric Antigen Cancer Bystander Effect medicine.disease Xenograft Model Antitumor Assays Chimeric antigen receptor Disease Models Animal 030104 developmental biology medicine.anatomical_structure Treatment Outcome Oncology 030220 oncology & carcinogenesis Cancer research Immunotherapy CRISPR-Cas Systems Genetic Engineering |
Zdroj: | Cancer Discov |
Popis: | 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 |
Databáze: | OpenAIRE |
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