The CD155/TIGIT axis promotes and maintains immune evasion in neoantigen-expressing pancreatic cancer
Open accessAbstract
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.
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A combination of scRNA-seq, multiplex IHC, and CyTOF immune profiling showed an inverse relationship between suppressive myeloid populations and CD8 effector T cell infiltration.
“For example, combined scRNA-seq, multiplex IHC, and CyTOF immune profiling demonstrated an inverse correlation between suppressive myeloid populations and CD8 effector T cell infiltrations277.”
From Pancreatic cancer: Advances and challenges (2023) · cites this paper as [277]
The same analyses found signs of systemic CD8 T cell exhaustion, and network analysis pointed to TIGIT as a central immune-suppression node.
“These further identified that CD8 T cells show indications of systemic exhaustion, and a network analysis of potential checkpoint receptor-ligand pairing suggested TIGIT as a key node of immune-suppression.”
From Pancreatic cancer: Advances and challenges (2023) · cites this paper as [277]
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Pancreatic cancer: Advances and challenges
Halbrook, C. J., Lyssiotis, C. A., Pasca di Magliano, M., & Maitra, A. (2023) · Cell · doi:10.1016/j.cell.2023.02.014 · Cited by 1,321 · see citing works
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“Indeed, a 408 recent study demonstrated that CD155, a ligand for T-cell immunoreceptor with 409 immunoglobulin and ITIM domains (TIGIT), is highly expressed in human PDAC 410 tumors, and combination therapy including an agonistic anti-CD40 antibody and 411 coblockade of both PD-1 and TIGIT showed an enhanced effect on…”
BackgroundEpithelial and stromal co-evolution and complicity in pancreatic cancer
Hingorani, S. R. (2023) · Nature Reviews Cancer · doi:10.1038/s41568-022-00530-w · Cited by 108 · see citing works
PDAC as an immune evasive disease: can 3D model systems aid to tackle this clinical problem?
Narayanan, S., Vicent, S., & Ponz-Sarvisé, M. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.787249 · Cited by 24 · see citing works
- Authors
- Freed-Pastor, W. A., Lambert, L. J., Ely, Z. A., Pattada, N. B., Bhutkar, A., Eng, G., Mercer, K. L., Garcia, A. P., Lin, L., Rideout, W. M., Hwang, W. L., Schenkel, J. M., Jaeger, A. M., Bronson, R. T., Westcott, P. M. K., Hether, T. D., Divakar, P., Reeves, J. W., Deshpande, V., Delorey, T., Phillips, D., Yilmaz, O. H., Regev, A., & Jacks, T.
- Affiliations
- Harvard University (US)
- Koch Institute for Integrative Cancer Research At MIT (US)
- Massachusetts General Hospital (US)
- Broad Institute (US)
- Brigham and Women's Hospital (US)
- Nanostring Technologies (United States) (US)
- Corresponding author
- Jacks, Tyler
- ORCID
- Freed-Pastor, William A.
- Ely, Zackery A.
- Bhutkar, Arjun
- Eng, George
- Mercer, Kim L.
- Lin, Lin
- Rideout, William M.
- Hwang, William L.
- Schenkel, Jason M.
- Jaeger, Alex M.
- Bronson, Roderick T.
- Westcott, Peter M.K.
- Hether, Tyler D.
- Divakar, Prajan
- Reeves, Jason W.
- Deshpande, Vikram
- Delorey, Toni
- Phillips, Devan
- Yilmaz, Omer H.
- Regev, Aviv
- Jacks, Tyler
- Venue
- Cancer Cell
- Publisher
- Elsevier BV
- Published
- 2021-10
- Volume
- 39
- Issue
- 10
- Pages
- 1342-1360.e14
- ISSN
- 1535-6108 (ISSN-L)
- PMC
- PMC8511341
- OpenAlex
- W3189337473
- Cited by
- 273
- References
- 124
- Citations by year
- 2026: 42 · 2025: 58 · 2024: 50 · 2023: 70 · 2022: 45 · 2021: 7 · 2013: 1
- FWCI
- 15.73
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 375 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Cancer Cell (publishedVersion)
- SSRN Electronic Journal (acceptedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc-nd)
- Funders
- American Association for Cancer Research
- National Cancer Institute (P30-CA14051)
- Damon Runyon Cancer Research Foundation
- National Institutes of Health (T32GM007287)
- Howard Hughes Medical Institute
- Entertainment Industry Foundation
- Stand up to Cancer
- Broad Institute
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology
- Johnson and Johnson
- Lustgarten Foundation
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Keywords
- CD155, TIGIT, pancreatic ductal adenocarcinoma, immune evasion, neoantigens, CD8+ T cell dysfunction, CD40 agonism, combination immunotherapy, tumor-infiltrating lymphocytes
- MeSH terms
- Animals, Humans, Immunotherapy, Pancreatic Neoplasms, Receptors, Virus, Lymphocytes, Tumor-Infiltrating, Mice, Immune Evasion
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
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