To identify novel neoantigens, Cai et al. assembled an immunopeptidomics atlas from published tumor and normal tissue datasets. Non-canonical (non-coding; 15%) and canonical (85%) peptides exhibited similar tissue distribution and presentation. Tumor-derived peptides exhibited differential features compared to normal tissue-derived peptides, such as positively charged residues and basic AA anchors. Cancer- and tissue-specific machine learning models identified 2,523 immunogenic tumor-specific peptides (41% noncanonical), most of which were patient-specific. Three highly ranked candidate pan-cancer peptides induced proliferation and antitumor cytotoxic activity in T cells.

Contributed by Morgan Janes

ABSTRACT: Neoantigens have emerged as ideal targets for personalized cancer immunotherapy. We depict the pan-cancer peptide atlas by comprehensively collecting immunopeptidomics from 531 samples across 14 cancer and 29 normal tissues, and identify 389,165 canonical and 70,270 noncanonical peptides. We reveal that noncanonical peptides exhibit comparable presentation levels as canonical peptides across cancer types. Tumor-specific peptides exhibit significantly distinct biochemical characteristics compared with those observed in normal tissues. We further propose an immunopeptidomic-guided machine learning-based neoantigen screening pipeline (MaNeo) to prioritize neo-peptides as immunotherapy targets. Benchmark analysis reveals MaNeo results in the accurate identification of shared and tumor-specific canonical and noncanonical neo-peptides. Last, we use MaNeo to detect and validate three neo-peptides in cancer cell lines, which can effectively induce increased proliferation of active T cells and T cell responses to kill cancer cells but not damage healthy cells. The pan-cancer peptide atlas and proposed MaNeo pipeline hold great promise for the discovery of canonical and noncanonical neoantigens for cancer immunotherapies.

Author Info: (1) State Key Laboratory of Frigid Zone Cardiovascular Diseases (SKLFZCD), College of Bioinformatics Science and Technology, Harbin Medical University, Harbin 150081, China. (2) De

Author Info: (1) State Key Laboratory of Frigid Zone Cardiovascular Diseases (SKLFZCD), College of Bioinformatics Science and Technology, Harbin Medical University, Harbin 150081, China. (2) Department of Pharmacology (Key Laboratory of Cardiovascular Medicine Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, Heilongjiang 150081, PR China. (3) State Key Laboratory of Frigid Zone Cardiovascular Diseases (SKLFZCD), College of Bioinformatics Science and Technology, Harbin Medical University, Harbin 150081, China. (4) State Key Laboratory of Frigid Zone Cardiovascular Diseases (SKLFZCD), College of Bioinformatics Science and Technology, Harbin Medical University, Harbin 150081, China. (5) State Key Laboratory of Frigid Zone Cardiovascular Diseases (SKLFZCD), College of Bioinformatics Science and Technology, Harbin Medical University, Harbin 150081, China. (6) State Key Laboratory of Frigid Zone Cardiovascular Diseases (SKLFZCD), School of Interdisciplinary Medicine and Engineering, Harbin Medical University, Harbin, Heilongjiang 150081, China. (7) Department of Pharmacology (Key Laboratory of Cardiovascular Medicine Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, Heilongjiang 150081, PR China. (8) The Second Affiliated Hospital of Harbin Medical University, Harbin 150081, China. (9) Department of Radiation Oncology, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang 150040, China. (10) Department of Radiation Oncology, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang 150040, China. (11) Department of Pharmacology (Key Laboratory of Cardiovascular Medicine Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, Heilongjiang 150081, PR China. (12) State Key Laboratory of Frigid Zone Cardiovascular Diseases (SKLFZCD), College of Bioinformatics Science and Technology, Harbin Medical University, Harbin 150081, China. (13) State Key Laboratory of Frigid Zone Cardiovascular Diseases (SKLFZCD), School of Interdisciplinary Medicine and Engineering, Harbin Medical University, Harbin, Heilongjiang 150081, China. Department of Radiation Oncology, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang 150040, China.