Pancreatic cancer-restricted cryptic antigens are targets for T cell recognition

• 成果类型: Article
• 署名作者: Ely, Zackery A.; Kulstad, Zachary J.; Gunaydin, Gurcan; Addepalli, Sudarsana; Verzani, Eva K.; Casarrubios, Marta; Clauser, Karl R.; Wang, Xilin; Lippincott, Isabelle E.; Louvet, Cedric; Schmitt, Thomas; Kapner, Kevin S.; Agus, Miles P.; Hennessey, Connor J.; Cleary, James M.; Hadrup, Sine R.; Klaeger, Susan; Su, Jennifer; Jaeger, Alex M.; Wolpin, Brian M.; Raghavan, Srivatsan; Smith, Eric L.; Greenberg, Philip D.; Aguirre, Andrew J.; Abelin, Jennifer G.; Carr, Steven A.; Jacks, Tyler; Freed-Pastor, William A.
• 署名单位: Massachusetts Institute of Technology (MIT); Massachusetts Institute of Technology (MIT); Harvard University; Harvard University Medical Affiliates; Dana-Farber Cancer Institute; Harvard University; Massachusetts Institute of Technology (MIT); Broad Institute; Harvard University; Harvard Medical School; Fred Hutchinson Cancer Center; Technical University of Denmark; University of Washington; University of Washington Seattle; University of Washington; University of Washington Seattle; Columbia University; Roche Holding; Genentech; Roche Holding USA; H Lee Moffitt Cancer Center & Research Institute
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-13775
• DOI: 10.1126/science.adk3487
• 发表日期: 2025-05-08
• 关键词: gene-expression; noncoding rnas

摘要

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.