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Mutation-associated neoantigen (MANA) -specific CD8+ tumor-infiltrating lymphocytes (TIL) have been shown to express high levels of\n                    <jats:italic>CXCL13<\/jats:italic>\n                    and CD39 (\n                    <jats:italic>ENTPD1<\/jats:italic>\n                    ), and low IL-7 receptor (\n                    <jats:italic>IL7R<\/jats:italic>\n                    ) levels in many cancer types, but their collective relevance to T cell functionality has not been established. Here we present an integrative tool to identify MANA-specific TIL using weighted expression levels of these three genes in lung cancer and melanoma single-cell RNAseq datasets. Our three-gene \u201cMANAscore\u201d algorithm outperforms other RNAseq-based algorithms in identifying validated neoantigen-specific CD8+ clones, and accurately identifies TILs that recognize other classes of tumor antigens, including cancer testis antigens, endogenous retroviruses and viral oncogenes. Most of these TIL are characterized by a tissue resident memory gene expression program. Putative tumor-reactive cells (pTRC) identified via MANAscore in anti-PD-1-treated lung tumors had higher expression of checkpoint and cytotoxicity-related genes relative to putative non-tumor-reactive cells. pTRC in pathologically responding tumors showed distinguished gene expression patterns and trajectories. Collectively, we show that MANAscore is a robust tool that can greatly enrich candidate tumor-specific T cells and be used to understand the functional programming of tumor-reactive TIL.\n                  <\/jats:p>","DOI":"10.1038\/s41467-024-55059-3","type":"journal-article","created":{"date-parts":[[2025,2,3]],"date-time":"2025-02-03T05:03:17Z","timestamp":1738558997000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":27,"title":["A minimal gene set characterizes TIL specific for diverse tumor antigens across different cancer types"],"prefix":"10.1038","volume":"16","author":[{"given":"Zhen","family":"Zeng","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-3287-620X","authenticated-orcid":false,"given":"Tianbei","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiajia","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuai","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sydney","family":"Connor","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Boyang","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yimin","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jordan","family":"Wilson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dipika","family":"Singh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1092-1594","authenticated-orcid":false,"given":"Rima","family":"Kulikauskas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Candice D.","family":"Church","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas H.","family":"Pulliam","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saumya","family":"Jani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2784-963X","authenticated-orcid":false,"given":"Paul","family":"Nghiem","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0821-8587","authenticated-orcid":false,"given":"Suzanne L.","family":"Topalian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6925-6344","authenticated-orcid":false,"given":"Patrick M.","family":"Forde","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6215-1013","authenticated-orcid":false,"given":"Drew M.","family":"Pardoll","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6480-0141","authenticated-orcid":false,"given":"Hongkai","family":"Ji","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6295-8930","authenticated-orcid":false,"given":"Kellie N.","family":"Smith","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,2,3]]},"reference":[{"key":"55059_CR1","doi-asserted-by":"publisher","first-page":"568","DOI":"10.1038\/nature13954","volume":"515","author":"PC Tumeh","year":"2014","unstructured":"Tumeh, P. 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BKI-immuno-KNS\/MANAscore. https:\/\/doi.org\/10.5281\/zenodo.14031503, (2024).","DOI":"10.5281\/zenodo.14031503,"}],"container-title":["Nature Communications"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41467-024-55059-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41467-024-55059-3","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41467-024-55059-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,2,3]],"date-time":"2025-02-03T05:03:23Z","timestamp":1738559003000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41467-024-55059-3"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,2,3]]},"references-count":50,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["55059"],"URL":"https:\/\/doi.org\/10.1038\/s41467-024-55059-3","relation":{},"ISSN":["2041-1723"],"issn-type":[{"value":"2041-1723","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,2,3]]},"assertion":[{"value":"29 May 2024","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"27 November 2024","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"3 February 2025","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"P.M.F. receives research support from AstraZeneca, BioNtech, Bristol-Myers Squibb, Novartis, Regeneron, and has been a consultant for AstraZeneca, Amgen, Bristol-Myers Squibb, Iteos, Novartis, Star, Surface, Genentech, G1, Sanofi, Daiichi, Regeneron, Tavotek, VBL Therapeutics, Sankyo, and Janssen and serves on a data safety and monitoring board for Polaris. S.Y. receives research funding from Bristol-Myers Squibb\/Celgene, Janssen, and Cepheid, has served as a consultant for Cepheid, and owns founders\u2019 equity in Brahm Astra Therapeutics and Digital Harmonic. K.N.S. and D.M.P. have filed for patent protection on the MANAFEST technology (serial No. 16\/341,862). D.M.P. is a consultant for Compugen, Shattuck Labs, WindMIL, Tempest, Immunai, Bristol-Myers Squibb, Amgen, Janssen, Astellas, Rockspring Capital, Immunomic, Dracen and owns founders\u2019 equity in Clasp Therapeutics, WindMIL, Trex, Jounce, Enara, Tizona, Tieza, RAPT and receives research funding from Compugen, Bristol-Myers Squibb, and Enara. K.N.S. has received travel support\/honoraria from Illumina, Inc., receives research funding from Bristol-Myers Squibb, Abbvie, and Astra Zeneca, and owns founder\u2019s equity in Clasp Therapeutics. S.L.T receives consulting fees from Bristol Myers Squibb, Dragonfly Therapeutics, PathAI, and Regeneron; receives research grants from Bristol Myers Squibb; has stock options in Dragonfly Therapeutics; and has a patent related to the treatment of MSI-high cancers with anti-PD-1.The terms of all these arrangements are being managed by Johns Hopkins University in accordance with its conflict-of-interest policies. All other authors declare that they have no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"1070"}}