{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T00:57:57Z","timestamp":1791593877128,"version":"4.3.4"},"reference-count":65,"publisher":"American Society of Hematology","issue":"9","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2020,2,27]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>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 &amp;gt;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-cell malignancies, 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.<\/jats:p>","DOI":"10.1182\/blood.2019002121","type":"journal-article","created":{"date-parts":[[2019,12,12]],"date-time":"2019-12-12T10:52:23Z","timestamp":1576147943000},"page":"597-609","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":212,"title":["Integrated drug profiling and CRISPR screening identify essential pathways for CAR T-cell cytotoxicity"],"prefix":"10.1182","volume":"135","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8084-0282","authenticated-orcid":false,"given":"Olli","family":"Dufva","sequence":"first","affiliation":[{"name":"Hematology Research Unit Helsinki, Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland;"},{"name":"Translational Immunology Research Program and"},{"name":"Department of Clinical Chemistry and Hematology, University of Helsinki, Helsinki, Finland;"},{"name":"iCAN Digital Precision Cancer Medicine Flagship, Helsinki, Finland;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan","family":"Koski","sequence":"first","affiliation":[{"name":"Finnish Red Cross Blood Service, Helsinki, Finland;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pilvi","family":"Maliniemi","sequence":"first","affiliation":[{"name":"Finnish Red Cross Blood Service, Helsinki, Finland;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aleksandr","family":"Ianevski","sequence":"first","affiliation":[{"name":"Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland;"},{"name":"Helsinki Institute for Information Technology, Department of Computer Science, Aalto University, Espoo, Finland;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jay","family":"Klievink","sequence":"first","affiliation":[{"name":"Hematology Research Unit Helsinki, Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland;"},{"name":"Translational Immunology Research Program and"},{"name":"Department of Clinical Chemistry and Hematology, University of Helsinki, Helsinki, Finland;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Judith","family":"Leitner","sequence":"first","affiliation":[{"name":"Centre for Pathophysiology, Infectiology and Immunology, Institute of Immunology, Medical University of Vienna, Vienna, Austria;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Petri","family":"P\u00f6l\u00f6nen","sequence":"first","affiliation":[{"name":"Institute of Biomedicine, School of Medicine, University of Eastern Finland, Kuopio, Finland; 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