MassIVE MSV000096853

Partial Public PXD059832

Cancer-restricted cryptic antigens are targets for T cell recognition

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Description

Ely ZA, Kulstad ZJ, Gunaydin G, Addepalli S, Verzani EK, Casarrubios M, Clauser KR, Wang X, Lippincott IE, Louvet C, Schmitt T, Kapner KS, Agus MP, Hennessey CJ, Cleary JM, Hadrup SR, Klaeger S, Su J, Jaeger AM, Wolpin BM, Raghavan S, Smith EL, Greenberg PD, Aguirre AJ, Abelin JG, Carr SA, Jacks T, Freed-Pastor WA. 2025 Translation of the non-coding genome in cancer can generate cryptic peptides capable of presentation by human leukocyte antigen class I (HLA-I); however, the cancer-specificity and immunogenicity of non-canonical HLA-I-bound peptides (ncHLAp) is not fully understood. Using personalized proteogenomics coupled with high-resolution immunopeptidomics, we found that cryptic peptides are abundant in the pancreatic cancer immunopeptidome. We developed a novel translation-centric pipeline and discovered that ~30% of ncHLAp exhibit bona fide cancer-restricted translation, with a substantial subset shared among patients. Cancer-restricted ncHLAp demonstrated immunogenic potential in a highly sensitive ex vivo T cell priming platform. ncHLAp-reactive, TCR-redirected T cells (TCR-T) exhibit robust tumoricidal activity against patient-derived pancreatic cancer organoids. These findings demonstrate that dysregulated translation in pancreatic cancer can give rise to recurrent cancer-restricted ncHLAp capable of recognition by cytotoxic T cells. We anticipate future therapeutic strategies for pancreatic cancer and other solid tumors will include targeting cryptic antigens. [doi:10.25345/C5S17T519] [dataset license: CC0 1.0 Universal (CC0 1.0)]

Keywords: immunopeptidome ; pancreatic ductal adenocarcinoma ; non-canonical ORF ; DatasetType:Proteomics

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Principal Investigators:
(in alphabetical order) 		Steven A. Carr, Broad Institute of MIT and Harvard, United States
Submitting User: clauser
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