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Systematic Interrogation of Tumor Cell Resistance to Chimeric Antigen Receptor T-cell Therapy in Pancreatic Cancer
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 inve...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Association for Cancer Research
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9929516/ https://www.ncbi.nlm.nih.gov/pubmed/36548402 http://dx.doi.org/10.1158/0008-5472.CAN-22-2245 |
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author | Hagel, Kimberly R. Arafeh, Rand Gang, Sydney Arnoff, Taylor E. Larson, Rebecca C. Doench, John G. Mathewson, Nathan D. Wucherpfennig, Kai W. Maus, Marcela V. Hahn, William C. |
author_facet | Hagel, Kimberly R. Arafeh, Rand Gang, Sydney Arnoff, Taylor E. Larson, Rebecca C. Doench, John G. Mathewson, Nathan D. Wucherpfennig, Kai W. Maus, Marcela V. Hahn, William C. |
author_sort | Hagel, Kimberly R. |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-9929516 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | American Association for Cancer Research |
record_format | MEDLINE/PubMed |
spelling | pubmed-99295162023-02-16 Systematic Interrogation of Tumor Cell Resistance to Chimeric Antigen Receptor T-cell Therapy in Pancreatic Cancer Hagel, Kimberly R. Arafeh, Rand Gang, Sydney Arnoff, Taylor E. Larson, Rebecca C. Doench, John G. Mathewson, Nathan D. Wucherpfennig, Kai W. Maus, Marcela V. Hahn, William C. Cancer Res Tumor Biology and Immunology 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. American Association for Cancer Research 2023-02-15 2022-12-22 /pmc/articles/PMC9929516/ /pubmed/36548402 http://dx.doi.org/10.1158/0008-5472.CAN-22-2245 Text en ©2022 The Authors; Published by the American Association for Cancer Research https://creativecommons.org/licenses/by-nc-nd/4.0/This open access article is distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) license. |
spellingShingle | Tumor Biology and Immunology Hagel, Kimberly R. Arafeh, Rand Gang, Sydney Arnoff, Taylor E. Larson, Rebecca C. Doench, John G. Mathewson, Nathan D. Wucherpfennig, Kai W. Maus, Marcela V. Hahn, William C. Systematic Interrogation of Tumor Cell Resistance to Chimeric Antigen Receptor T-cell Therapy in Pancreatic Cancer |
title | Systematic Interrogation of Tumor Cell Resistance to Chimeric Antigen Receptor T-cell Therapy in Pancreatic Cancer |
title_full | Systematic Interrogation of Tumor Cell Resistance to Chimeric Antigen Receptor T-cell Therapy in Pancreatic Cancer |
title_fullStr | Systematic Interrogation of Tumor Cell Resistance to Chimeric Antigen Receptor T-cell Therapy in Pancreatic Cancer |
title_full_unstemmed | Systematic Interrogation of Tumor Cell Resistance to Chimeric Antigen Receptor T-cell Therapy in Pancreatic Cancer |
title_short | Systematic Interrogation of Tumor Cell Resistance to Chimeric Antigen Receptor T-cell Therapy in Pancreatic Cancer |
title_sort | systematic interrogation of tumor cell resistance to chimeric antigen receptor t-cell therapy in pancreatic cancer |
topic | Tumor Biology and Immunology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9929516/ https://www.ncbi.nlm.nih.gov/pubmed/36548402 http://dx.doi.org/10.1158/0008-5472.CAN-22-2245 |
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