The CD155/TIGIT axis promotes and maintains immune evasion in neoantigen-expressing pancreatic cancer
The CD155/TIGIT axis can be co-opted during immune evasion in chronic viral infections and cancer. Pancreatic adenocarcinoma (PDAC) is a highly lethal malignancy, and immune-based strategies to combat this disease have been largely unsuccessful to date. We corroborate prior reports that a substantia...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier BV
2022
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| Online Access: | https://hdl.handle.net/1721.1/146821 |
| _version_ | 1811079783786741760 |
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| author | Freed-Pastor, William A Lambert, Laurens J Ely, Zackery A Pattada, Nimisha B Bhutkar, Arjun Eng, George Mercer, Kim L Garcia, Ana P Lin, Lin Rideout, William M Hwang, William L Schenkel, Jason M Jaeger, Alex M Bronson, Roderick T Westcott, Peter MK Hether, Tyler D Divakar, Prajan Reeves, Jason W Deshpande, Vikram Delorey, Toni Phillips, Devan Yilmaz, Omer H Regev, Aviv Jacks, Tyler |
| author2 | Massachusetts Institute of Technology. Department of Biology |
| author_facet | Massachusetts Institute of Technology. Department of Biology Freed-Pastor, William A Lambert, Laurens J Ely, Zackery A Pattada, Nimisha B Bhutkar, Arjun Eng, George Mercer, Kim L Garcia, Ana P Lin, Lin Rideout, William M Hwang, William L Schenkel, Jason M Jaeger, Alex M Bronson, Roderick T Westcott, Peter MK Hether, Tyler D Divakar, Prajan Reeves, Jason W Deshpande, Vikram Delorey, Toni Phillips, Devan Yilmaz, Omer H Regev, Aviv Jacks, Tyler |
| author_sort | Freed-Pastor, William A |
| collection | MIT |
| description | The CD155/TIGIT axis can be co-opted during immune evasion in chronic viral infections and cancer. Pancreatic adenocarcinoma (PDAC) is a highly lethal malignancy, and immune-based strategies to combat this disease have been largely unsuccessful to date. We corroborate prior reports that a substantial portion of PDAC harbors predicted high-affinity MHC class I-restricted neoepitopes and extend these findings to advanced/metastatic disease. Using multiple preclinical models of neoantigen-expressing PDAC, we demonstrate that intratumoral neoantigen-specific CD8+ T cells adopt multiple states of dysfunction, resembling those in tumor-infiltrating lymphocytes of PDAC patients. Mechanistically, genetic and/or pharmacologic modulation of the CD155/TIGIT axis was sufficient to promote immune evasion in autochthonous neoantigen-expressing PDAC. Finally, we demonstrate that the CD155/TIGIT axis is critical in maintaining immune evasion in PDAC and uncover a combination immunotherapy (TIGIT/PD-1 co-blockade plus CD40 agonism) that elicits profound anti-tumor responses in preclinical models, now poised for clinical evaluation. |
| first_indexed | 2024-09-23T11:20:24Z |
| format | Article |
| id | mit-1721.1/146821 |
| institution | Massachusetts Institute of Technology |
| language | English |
| last_indexed | 2024-09-23T11:20:24Z |
| publishDate | 2022 |
| publisher | Elsevier BV |
| record_format | dspace |
| spelling | mit-1721.1/1468212022-12-10T03:29:09Z The CD155/TIGIT axis promotes and maintains immune evasion in neoantigen-expressing pancreatic cancer Freed-Pastor, William A Lambert, Laurens J Ely, Zackery A Pattada, Nimisha B Bhutkar, Arjun Eng, George Mercer, Kim L Garcia, Ana P Lin, Lin Rideout, William M Hwang, William L Schenkel, Jason M Jaeger, Alex M Bronson, Roderick T Westcott, Peter MK Hether, Tyler D Divakar, Prajan Reeves, Jason W Deshpande, Vikram Delorey, Toni Phillips, Devan Yilmaz, Omer H Regev, Aviv Jacks, Tyler Massachusetts Institute of Technology. Department of Biology The CD155/TIGIT axis can be co-opted during immune evasion in chronic viral infections and cancer. Pancreatic adenocarcinoma (PDAC) is a highly lethal malignancy, and immune-based strategies to combat this disease have been largely unsuccessful to date. We corroborate prior reports that a substantial portion of PDAC harbors predicted high-affinity MHC class I-restricted neoepitopes and extend these findings to advanced/metastatic disease. Using multiple preclinical models of neoantigen-expressing PDAC, we demonstrate that intratumoral neoantigen-specific CD8+ T cells adopt multiple states of dysfunction, resembling those in tumor-infiltrating lymphocytes of PDAC patients. Mechanistically, genetic and/or pharmacologic modulation of the CD155/TIGIT axis was sufficient to promote immune evasion in autochthonous neoantigen-expressing PDAC. Finally, we demonstrate that the CD155/TIGIT axis is critical in maintaining immune evasion in PDAC and uncover a combination immunotherapy (TIGIT/PD-1 co-blockade plus CD40 agonism) that elicits profound anti-tumor responses in preclinical models, now poised for clinical evaluation. 2022-12-09T18:47:12Z 2022-12-09T18:47:12Z 2021 2022-12-09T18:41:24Z Article http://purl.org/eprint/type/JournalArticle https://hdl.handle.net/1721.1/146821 Freed-Pastor, William A, Lambert, Laurens J, Ely, Zackery A, Pattada, Nimisha B, Bhutkar, Arjun et al. 2021. "The CD155/TIGIT axis promotes and maintains immune evasion in neoantigen-expressing pancreatic cancer." Cancer Cell, 39 (10). en 10.1016/J.CCELL.2021.07.007 Cancer Cell Creative Commons Attribution-NonCommercial-NoDerivs License http://creativecommons.org/licenses/by-nc-nd/4.0/ application/pdf Elsevier BV PMC |
| spellingShingle | Freed-Pastor, William A Lambert, Laurens J Ely, Zackery A Pattada, Nimisha B Bhutkar, Arjun Eng, George Mercer, Kim L Garcia, Ana P Lin, Lin Rideout, William M Hwang, William L Schenkel, Jason M Jaeger, Alex M Bronson, Roderick T Westcott, Peter MK Hether, Tyler D Divakar, Prajan Reeves, Jason W Deshpande, Vikram Delorey, Toni Phillips, Devan Yilmaz, Omer H Regev, Aviv Jacks, Tyler The CD155/TIGIT axis promotes and maintains immune evasion in neoantigen-expressing pancreatic cancer |
| title | The CD155/TIGIT axis promotes and maintains immune evasion in neoantigen-expressing pancreatic cancer |
| title_full | The CD155/TIGIT axis promotes and maintains immune evasion in neoantigen-expressing pancreatic cancer |
| title_fullStr | The CD155/TIGIT axis promotes and maintains immune evasion in neoantigen-expressing pancreatic cancer |
| title_full_unstemmed | The CD155/TIGIT axis promotes and maintains immune evasion in neoantigen-expressing pancreatic cancer |
| title_short | The CD155/TIGIT axis promotes and maintains immune evasion in neoantigen-expressing pancreatic cancer |
| title_sort | cd155 tigit axis promotes and maintains immune evasion in neoantigen expressing pancreatic cancer |
| url | https://hdl.handle.net/1721.1/146821 |
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