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

Abstract

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.

• Authors: Kimberly R Hagel, Rand Arafeh, Sydney Gang, Taylor E Arnoff, Rebecca C Larson, John G Doench, Nathan D Mathewson, Kai W Wucherpfennig, Marcela V Maus, William C Hahn
• Journal: Cancer research (Cancer Res) Vol. 83 Issue 4 Pg. 613-625 (02 15 2023) ISSN: 1538-7445 [Electronic] United States
• PMID: 36548402 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2022 The Authors; Published by the American Association for Cancer Research.

Chemical References

• Receptors, Antigen, T-Cell
• Receptors, Chimeric Antigen

Topics

• Humans
• Cell Line, Tumor
• Cell- and Tissue-Based Therapy
• Immunotherapy, Adoptive
• Pancreatic Neoplasms (pathology, therapy)
• Receptors, Antigen, T-Cell
• Receptors, Chimeric Antigen (genetics, therapeutic use)