Journal
BLOOD
Volume 135, Issue 9, Pages 597-609Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood.2019002121
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Funding
- Finnish Association of Hematology
- Finnish Red Cross Blood Service
- Institute for Molecular Medicine Finland
- Cancer Foundation Finland
- Sigrid Juselius Foundation
- Relander Foundation
- state funding for university-level health research in Finland
- HiLife fellow funds from the University of Helsinki
- Biomedicum Helsinki Foundation
- Finnish Medical Society
- Finnish Pediatric Cancer Foundation
- Vare Pediatric Research Foundation
- Orion Research Foundation
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Chimeric antigen receptor (CAR) T-cell therapy has proven effective in relapsed and refractory B-cell malignancies, but resistance and relapses still occur. Better understanding of mechanisms influencing CAR T-cell cytotoxicity and the potential for modulation using small-molecule drugs could improve current immunotherapies. Here, we systematically investigated druggable mechanisms of CAR T-cell cytotoxicity using >500 small-molecule drugs and genome-scale CRISPR-Cas9 loss-of-function screens. We identified several tyrosine kinase inhibitors that inhibit CAR T-cell cytotoxicity by impairing T-cell signaling transcriptional activity. In contrast, the apoptotic modulator drugs SMAC mimetics sensitized B-cell acute lymphoblastic leukemia and diffuse large B-cell lymphoma cells to anti-CD19 CAR T cells. CRISPR screens identified death receptor signaling through FADD and TNFRSF10B (TRAIL-R2) as a key mediator of CAR T-cell cytotoxicity and elucidated the RIPK1-dependent mechanism of sensitization by SMAC mimetics. Death receptor expression varied across genetic subtypes of B-cellmalignancies, suggesting a link between mechanisms of CAR T-cell cytotoxicity and cancer genetics. These results implicate death receptor signaling as an important mediator of cancer cell sensitivity to CAR T-cell cytotoxicity, with potential for pharmacological targeting to enhance cancer immunotherapy. The screening data provide a resource of immunomodulatory properties of cancer drugs and genetic mechanisms influencing CAR T-cell cytotoxicity.
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