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

William A Freed-Pastor; Laurens J Lambert; Zackery A Ely; Nimisha B Pattada; Arjun Bhutkar; George Eng; Kim L Mercer; Ana P Garcia; Lin Lin; William M Rideout 3rd; William L Hwang; Jason M Schenkel; Alex M Jaeger; Roderick T Bronson; Peter M K Westcott; Tyler D Hether; Prajan Divakar; Jason W Reeves; Vikram Deshpande; Toni Delorey; Devan Phillips; Omer H Yilmaz; Aviv Regev; Tyler Jacks

doi:10.1016/j.ccell.2021.07.007

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.

Authors

William A Freed-Pastor¹, Laurens J Lambert², Zackery A Ely², Nimisha B Pattada³, Arjun Bhutkar³, George Eng⁴, Kim L Mercer³, Ana P Garcia³, Lin Lin³, William M Rideout 3rd³, William L Hwang⁵, Jason M Schenkel⁶, Alex M Jaeger³, Roderick T Bronson³, Peter M K Westcott³, Tyler D Hether⁷, Prajan Divakar⁷, Jason W Reeves⁷, Vikram Deshpande⁸, Toni Delorey⁹, Devan Phillips⁹, Omer H Yilmaz¹⁰, Aviv Regev¹¹, Tyler Jacks¹²

Affiliations

¹ David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
² David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
³ David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
⁴ David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Pathology, Massachusetts General Hospital, Boston, MA 02114, USA.
⁵ David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
⁶ David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
⁷ NanoString Inc., Seattle, WA 98109, USA.
⁸ Department of Pathology, Massachusetts General Hospital, Boston, MA 02114, USA.
⁹ Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
¹⁰ David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Pathology, Massachusetts General Hospital, Boston, MA 02114, USA.
¹¹ David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
¹² David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. Electronic address: tjacks@mit.edu.

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

Abstract

Publication types

MeSH terms

Substances

Grants and funding