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A Critical Role for Fas-Mediated Off-Target Tumor Killing in T-cell Immunotherapy

Upadhyay, Ranjan (författare)
Department of Medicine, Division of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, USA; Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, USA; Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York.
Boiarsky, Jonathan A. (författare)
Department of Medicine, Division of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, New York;Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York.;3Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, USA
Pantsulaia, Gvantsa (författare)
Department of Medicine, Division of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, USA; Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, USA; Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, USA
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Svensson-Arvelund, Judit, 1982- (författare)
Department of Medicine, Division of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, USA; Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, USA; Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, USA
Lin, Matthew J. (författare)
Department of Medicine, Division of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, USA; Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York.;3Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, USA
Wroblewska, Aleksandra (författare)
Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, USA; Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, USA; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, USA
Bhalla, Sherry (författare)
Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, USA; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, USA
Scholler, Nathalie (författare)
Kite Pharma, Santa Monica, California, UA
Bot, Adrian (författare)
5Kite Pharma, Santa Monica, California.
Rossi, John M. (författare)
Kite Pharma, Santa Monica, California, USA
Sadek, Norah (författare)
Department of Medicine, Division of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, USA; Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York.;3Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, USA
Parekh, Samir (författare)
Department of Medicine, Division of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, USA; Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York.;3Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, USA
Lagana, Alessandro (författare)
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, USA
Baccarini, Alessia (författare)
Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, USA; Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York.;4Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, USA
Merad, Miriam (författare)
Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New YoRK, USA; Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York.;6Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, USA
Brown, Brian D. (författare)
Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, USA; Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York.;Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, USA
Brody, Joshua D. (författare)
Department of Medicine, Division of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, New York.;2Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York.;3Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York.
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Department of Medicine, Division of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, USA; Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, USA; Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York Department of Medicine, Division of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, New York;Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York.;3Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, USA (creator_code:org_t)
2021-03-02
2021
Engelska.
Ingår i: Cancer Discovery. - : American Association For Cancer Research (AACR). - 2159-8274 .- 2159-8290. ; 11:3, s. 599-613
Relaterad länk:
https://www.ncbi.nlm...
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https://urn.kb.se/re...
https://doi.org/10.1...
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  • Tidskriftsartikel (refereegranskat)
Abstract Ämnesord
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  • 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.

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska och farmaceutiska grundvetenskaper -- Immunologi inom det medicinska området (hsv//swe)
MEDICAL AND HEALTH SCIENCES  -- Basic Medicine -- Immunology in the medical area (hsv//eng)

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