The CD155/TIGIT axis promotes and maintains immune evasion in neoantigen-expressing pancreatic cancer

Cancer Cell. 2021 Oct 11;39(10):1342-1360.e14. doi: 10.1016/j.ccell.2021.07.007. Epub 2021 Aug 5.

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.

Keywords: CD155; TIGIT; immune evasion; immunotherapy; pancreatic cancer.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Humans
  • Immune Evasion / immunology*
  • Immunotherapy / methods*
  • Lymphocytes, Tumor-Infiltrating / metabolism*
  • Mice
  • Pancreatic Neoplasms / immunology*
  • Receptors, Virus / immunology*

Substances

  • Receptors, Virus
  • poliovirus receptor

Supplementary concepts

  • Pancreatic Carcinoma