Pancreatic cancer–restricted cryptic antigens are targets for T cell recognition
Translation of the noncoding genome in cancer can generate cryptic (noncanonical) peptides capable of presentation by human leukocyte antigen class I (HLA-I); however, the cancer specificity and immunogenicity of noncanonical HLA-I-bound peptides (ncHLAp) are incompletely understood. Using high-resolution immunopeptidomics, we discovered that cryptic peptides are abundant in the pancreatic cancer immunopeptidome. Approximately 30% of ncHLAp exhibited cancer-restricted translation, and a substantial subset were shared among patients. Cancer-restricted ncHLAp displayed robust immunogenic potential in a sensitive ex vivo T cell priming platform. ncHLAp-reactive, T cell receptor-redirected T cells exhibited tumoricidal activity against patient-derived pancreatic cancer organoids. These findings demonstrate that pancreatic cancer harbors cancer-restricted ncHLAp that can be recognized by cytotoxic T cells. Future therapeutic strategies for pancreatic cancer, and potentially other solid tumors, may include targeting cryptic antigens.
Authors
- Marta Casarrubios (ORCID: https://orcid.org/0000-0002-2872-9552)
- Karl R. Clauser (ORCID: https://orcid.org/0000-0002-1052-9456)
- Kevin S. Kapner (ORCID: https://orcid.org/0000-0002-2306-2373)
- X Wang
- Zachary Kulstad (ORCID: https://orcid.org/0009-0007-2253-6366)
- James M. Cleary (ORCID: https://orcid.org/0000-0001-7213-3951)
- Miles Agus (ORCID: https://orcid.org/0009-0001-3533-6466)
- Connor J. Hennessey (ORCID: https://orcid.org/0000-0002-5579-1220)
- Jennifer G. Abelin (ORCID: https://orcid.org/0000-0001-5262-7241)
- Srivatsan Raghavan (ORCID: https://orcid.org/0000-0002-5374-9918)
- Philip D. Greenberg (ORCID: https://orcid.org/0000-0003-3812-647X)
- Susan Klaeger (ORCID: https://orcid.org/0000-0002-0074-5163)
- Sine Reker Hadrup (ORCID: https://orcid.org/0000-0002-5937-4344)
- Gürcan Günaydın (ORCID: https://orcid.org/0000-0002-6751-2217)
- Steven A. Carr (ORCID: https://orcid.org/0000-0002-7203-4299)
- Thomas M. Schmitt (ORCID: https://orcid.org/0000-0002-0736-4195)
- Alex M. Jaeger (ORCID: https://orcid.org/0000-0002-4319-4330)
- Brian M. Wolpin (ORCID: https://orcid.org/0000-0002-0455-1032)
- Eva K. Verzani (ORCID: https://orcid.org/0009-0004-0846-4878)
- Jennifer Su (ORCID: https://orcid.org/0000-0003-1798-6542)
- Cédric Louvet (ORCID: https://orcid.org/0000-0002-5668-2448)
- Tyler Jacks (ORCID: https://orcid.org/0000-0001-5785-8911)
- Andrew J. Aguirre (ORCID: https://orcid.org/0000-0002-0701-6203)
- William A. Freed-Pastor (ORCID: https://orcid.org/0000-0002-7377-2111)
- Zackery A. Ely (ORCID: https://orcid.org/0000-0002-9694-0341)
- Eric L. Smith (ORCID: https://orcid.org/0000-0002-0296-7587)
- Sudarsana Addepalli
- Isabelle E Lippincott
Institutions
- Broad Institute (US)
- Harvard University (US)
- University of Washington (US)
- University of Washington Medical Center (US)
- Pancreatic Cancer Action Network (US)
- Fred Hutch Cancer Center (US)
- Dana-Farber Cancer Institute (US)
- Massachusetts Institute of Technology (US)
- Technical University of Denmark (DK)
Publication Details
- Journal
- Science
- Published
- 2025-05-08
- DOI
- https://doi.org/10.1126/science.adk3487
- Citations
- 36
- Primary Topic
- vaccines and immunoinformatics approaches
- Type
- article
- Field-Weighted Citation Impact
- 29.02