Systematic Interrogation of Tumor Cell Resistance to Chimeric Antigen Receptor T-cell Therapy in Pancreatic Cancer.

Autor:	Hagel KR; Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.; Broad Institute of MIT and Harvard, Cambridge, Massachusetts., Arafeh R; Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.; Broad Institute of MIT and Harvard, Cambridge, Massachusetts., Gang S; Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts., Arnoff TE; Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts., Larson RC; Cellular Immunotherapy Program, Cancer Center, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts., Doench JG; Broad Institute of MIT and Harvard, Cambridge, Massachusetts., Mathewson ND; Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.; Broad Institute of MIT and Harvard, Cambridge, Massachusetts., Wucherpfennig KW; Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.; Broad Institute of MIT and Harvard, Cambridge, Massachusetts., Maus MV; Cellular Immunotherapy Program, Cancer Center, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts., Hahn WC; Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.; Broad Institute of MIT and Harvard, Cambridge, Massachusetts.; Brigham and Women's Hospital, Boston, Massachusetts.
Jazyk:	angličtina
Zdroj:	Cancer research [Cancer Res] 2023 Feb 15; Vol. 83 (4), pp. 613-625.
DOI:	10.1158/0008-5472.CAN-22-2245
Abstrakt:	Chimeric antigen receptor (CAR) T-cell therapy can lead to dramatic clinical responses in B-cell malignancies. However, early clinical trials with CAR T-cell therapy in non-B-cell malignancies have been disappointing to date, suggesting that tumor-intrinsic features contribute to resistance. To investigate tumor-intrinsic modes of resistance, we performed genome scale CRISPR-Cas9 screens in mesothelin (MSLN)-expressing pancreatic cancer cells. Co-culture with MSLN-targeting CAR T cells identified both antigen-dependent and antigen-independent modes of resistance. In particular, loss of the majority of the genes involved in the pathway responsible for GPI-anchor biosynthesis and attachment abrogated the ability of CAR T cells to target pancreatic cancer cells, suggesting that disruption of this pathway may permit MSLN CAR T-cell evasion in the clinic. Antigen-independent mediators of CAR T-cell response included members of the death receptor pathway as well as genes that regulate tumor transcriptional responses, including TFAP4 and INTS12. TFAP4-mediated CAR T resistance depended on the NFκB transcription factor p65, indicating that tumor resistance to CAR T-cell therapy likely involves alterations in tumor-intrinsic states. Overall, this study uncovers multiple antigen-dependent and -independent mechanisms of CAR T-cell evasion by pancreatic cancer, paving the way for overcoming resistance in this disease that is notoriously refractory to immunotherapy. Significance: The identification and validation of key determinants of CAR T-cell response in pancreatic cancer provide insights into the landscape of tumor cell intrinsic resistance mechanisms and into approaches to improve therapeutic efficacy. (©2022 The Authors; Published by the American Association for Cancer Research.)
Databáze:	MEDLINE
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