The CD155/TIGIT axis promotes and maintains immune evasion in neoantigen-expressing pancreatic cancer
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nihms-1730102.pdf
Description
Accepted version
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3.21 MB
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Author(s)
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
Date Issued
2021
Journal
Cancer Cell
Publisher
Elsevier BV
Citation
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).
Version
Author's final manuscript
Abstract
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.
MIT Department
Massachusetts Institute of Technology. Department of Biology
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Creative Commons Attribution-NonCommercial-NoDerivs License
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DOI of Published Version
https://doi.org/10.1016/J.CCELL.2021.07.007
