Authors: 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
Published: 2025-05-29
Source: Full article
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.