{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,27]],"date-time":"2026-02-27T06:20:55Z","timestamp":1772173255765,"version":"3.50.1"},"update-to":[{"DOI":"10.1371\/journal.pcbi.1010976","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2023,5,3]],"date-time":"2023-05-03T00:00:00Z","timestamp":1683072000000}}],"reference-count":59,"publisher":"Public Library of Science (PLoS)","issue":"4","license":[{"start":{"date-parts":[[2023,4,21]],"date-time":"2023-04-21T00:00:00Z","timestamp":1682035200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["R35 GM119661"],"award-info":[{"award-number":["R35 GM119661"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.ploscompbiol.org"],"crossmark-restriction":false},"short-container-title":["PLoS Comput Biol"],"abstract":"<jats:p>Predator-prey theory is commonly used to describe tumor growth in the presence of selective pressure from the adaptive immune system. These interactions are mediated by the tumor immunopeptidome (what the tumor \u201cshows\u201d the body) and the T-cell receptor (TCR) repertoire (how well the body \u201csees\u201d cancer cells). The tumor immunopeptidome comprises neoantigens which can be gained and lost throughout tumorigenesis and treatment. Heterogeneity in the immunopeptidome is predictive of poor response to immunotherapy in some tumor types, suggesting that the TCR repertoire is unable to support a fully polyclonal response against every neoantigen. Importantly, while tumor and T-cell populations are known to compete with each other for intratumoral resources, whether between-lineage competition among peripheral T cells influences the TCR repertoire is unknown and difficult to interrogate experimentally. Computational models may offer a way to investigate these phenomena and deepen our understanding of the tumor-immune axis. Here, we construct a predator-prey-like model and calibrate it to preclinical and clinical data to describe tumor growth and immunopeptidome diversification. Simultaneously, we model the expansion of antigen-specific T-cell lineages and their consumption of both lineage-specific antigenic resources and lineage-agnostic, shared resources. This predator-prey-like framework accurately described clinically observed immunopeptidomes; recapitulated response-associated effects of immunotherapy, including immunoediting; and allowed exploration of treatment of tumors with varying growth and mutation rates.<\/jats:p>","DOI":"10.1371\/journal.pcbi.1010976","type":"journal-article","created":{"date-parts":[[2023,4,21]],"date-time":"2023-04-21T13:58:24Z","timestamp":1682085504000},"page":"e1010976","update-policy":"https:\/\/doi.org\/10.1371\/journal.pcbi.corrections_policy","source":"Crossref","is-referenced-by-count":1,"title":["A multispecies framework for modeling adaptive immunity and immunotherapy in cancer"],"prefix":"10.1371","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4359-8271","authenticated-orcid":true,"given":"Timothy","family":"Qi","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Benjamin 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Receptors","volume":"11","author":"CH Lee","year":"2020","journal-title":"Front Immunol"},{"key":"pcbi.1010976.ref053","doi-asserted-by":"crossref","first-page":"214","DOI":"10.1016\/j.jtbi.2015.10.016","article-title":"How many TCR clonotypes does a body maintain?","volume":"389","author":"G Lythe","year":"2016","journal-title":"J Theor Biol"},{"key":"pcbi.1010976.ref054","unstructured":"Rohatgi A. WebPlotDigitizer 2022."},{"key":"pcbi.1010976.ref055","unstructured":"Amin MB, American Joint Committee on Cancer, American Cancer Society, editors. AJCC cancer staging manual. Eight edition \/ editor-in-chief, Mahul B. Amin, MD, FCAP; editors, Stephen B. Edge, MD, FACS [and 16 others]; Donna M. Gress, RHIT, CTR-Technical editor; Laura R. Meyer, CAPM-Managing editor. Chicago IL: American Joint Committee on Cancer, Springer; 2017."},{"key":"pcbi.1010976.ref056","doi-asserted-by":"crossref","first-page":"1517","DOI":"10.4049\/jimmunol.1600582","article-title":"Pan-Specific Prediction of Peptide\u2013MHC Class I Complex Stability, a Correlate of T Cell Immunogenicity","volume":"197","author":"M Rasmussen","year":"2016","journal-title":"J Immunol"},{"key":"pcbi.1010976.ref057","doi-asserted-by":"crossref","first-page":"e1007423","DOI":"10.1371\/journal.pcbi.1007423","article-title":"Cancer recurrence times from a branching process model","volume":"15","author":"S Avanzini","year":"2019","journal-title":"PLOS Comput Biol"},{"key":"pcbi.1010976.ref058","first-page":"134","article-title":"PRONOUNCE: randomized, open-label, phase III study of first-line pemetrexed + carboplatin followed by maintenance pemetrexed versus paclitaxel + carboplatin + bevacizumab followed by maintenance bevacizumab in patients ith advanced nonsquamous non-small-cell lung cancer","volume":"10","author":"RG Zinner","year":"2015","journal-title":"J Thorac Oncol Off Publ Int Assoc Study Lung Cancer"},{"key":"pcbi.1010976.ref059","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1111\/acel.12311","article-title":"Lymphocyte maintenance during healthy aging requires no substantial alterations in cellular turnover","volume":"14","author":"L Westera","year":"2015","journal-title":"Aging Cell"}],"updated-by":[{"DOI":"10.1371\/journal.pcbi.1010976","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2023,5,3]],"date-time":"2023-05-03T00:00:00Z","timestamp":1683072000000}}],"container-title":["PLOS Computational Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pcbi.1010976","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,5,3]],"date-time":"2023-05-03T13:46:39Z","timestamp":1683121599000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pcbi.1010976"}},"subtitle":[],"editor":[{"given":"Dominik","family":"Wodarz","sequence":"first","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]}],"short-title":[],"issued":{"date-parts":[[2023,4,21]]},"references-count":59,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2023,4,21]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pcbi.1010976","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2022.02.10.479985","asserted-by":"object"}]},"ISSN":["1553-7358"],"issn-type":[{"value":"1553-7358","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,4,21]]}}}