Pancreatic cancer–restricted cryptic antigens are targets for T cell recognition
- Zackery A. Ely
- Zachary J. Kulstad
- Gurcan Gunaydin
- Sudarsana Addepalli
- Eva K. Verzani
- Marta Casarrubios
- Karl R. Clauser
- Xilin Wang
- Isabelle E. Lippincott
- Cedric Louvet
- Thomas Schmitt
- Kevin S. Kapner
- Miles P. Agus
- Connor J. Hennessey
- James M. Cleary
- Sine R. Hadrup
- Susan Klaeger
- Jennifer Su
- Alex M. Jaeger
- Brian M. Wolpin
- Srivatsan Raghavan
- Eric L. Smith
- Philip D. Greenberg
- Andrew J. Aguirre
- Jennifer G. Abelin
- Steven A. Carr
- Tyler Jacks
- William A. Freed-Pastor
2025-05-29
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.