Julie F. Cheung, Brian G. Hunt, Shudipto Wahed, Elaine Cheng, Kelli A. Connolly, Srividhya Venkatesan, Jennifer L. Loza, Ishan Bansal, Eric Fagerberg, Emily A. Kessler, Clémence Riffard, Jessica Buck, John Attanasio, Emily R. Borr, Wei Wei, Ivana William, Brittany Fitzgerald, Nikhil S. Joshi
{"title":"Distinct T cell functions enable efficient immunoediting and prevent tumor emergence of developing sarcomas","authors":"Julie F. Cheung, Brian G. Hunt, Shudipto Wahed, Elaine Cheng, Kelli A. Connolly, Srividhya Venkatesan, Jennifer L. Loza, Ishan Bansal, Eric Fagerberg, Emily A. Kessler, Clémence Riffard, Jessica Buck, John Attanasio, Emily R. Borr, Wei Wei, Ivana William, Brittany Fitzgerald, Nikhil S. Joshi","doi":"10.1016/j.ccell.2025.09.005","DOIUrl":null,"url":null,"abstract":"T cells edit tumors by eliminating neoantigen-expressing tumor cells. Yet, how and when this is achieved remains uncertain. Using a murine sarcoma model with fluorescent neoantigens, we found that tumors developed later and in fewer T cell-sufficient mice (∼53% penetrance) than T cell-deficient mice (∼100%). With T cells, all emergent tumor cells had silenced neoantigens, but neoantigen-negative tumor cells were also present in every T cell-deficient mouse. This suggested silencing was necessary but not sufficient for outgrowth. Genetic removal of neoantigens restored tumor penetrance if implemented on day 5 post-tumor initiation, but not day 10, because CD8<sup>+</sup> and CD4<sup>+</sup> T cells infiltrated the tissue and eliminated most neoantigen-positive and -negative tumor cells within 8 days. Single-cell analyses on day-7 tumors showed oncogenic changes including increased proliferation and T cell-dependent upregulation of the IFNγ-response gene <em>Cd274</em> (PD-L1). T cell-depletion rescued both neoantigen-positive and -negative cells, while IFNγ blockade rescued only negative cells. This shows that T cells efficiently edit sarcomas of neoantigens and prevent early tumors via IFNγ-independent and IFNγ-dependent (bystander) mechanisms.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"2 1","pages":""},"PeriodicalIF":44.5000,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cancer Cell","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1016/j.ccell.2025.09.005","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CELL BIOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
T cells edit tumors by eliminating neoantigen-expressing tumor cells. Yet, how and when this is achieved remains uncertain. Using a murine sarcoma model with fluorescent neoantigens, we found that tumors developed later and in fewer T cell-sufficient mice (∼53% penetrance) than T cell-deficient mice (∼100%). With T cells, all emergent tumor cells had silenced neoantigens, but neoantigen-negative tumor cells were also present in every T cell-deficient mouse. This suggested silencing was necessary but not sufficient for outgrowth. Genetic removal of neoantigens restored tumor penetrance if implemented on day 5 post-tumor initiation, but not day 10, because CD8+ and CD4+ T cells infiltrated the tissue and eliminated most neoantigen-positive and -negative tumor cells within 8 days. Single-cell analyses on day-7 tumors showed oncogenic changes including increased proliferation and T cell-dependent upregulation of the IFNγ-response gene Cd274 (PD-L1). T cell-depletion rescued both neoantigen-positive and -negative cells, while IFNγ blockade rescued only negative cells. This shows that T cells efficiently edit sarcomas of neoantigens and prevent early tumors via IFNγ-independent and IFNγ-dependent (bystander) mechanisms.
期刊介绍:
Cancer Cell is a journal that focuses on promoting major advances in cancer research and oncology. The primary criteria for considering manuscripts are as follows:
Major advances: Manuscripts should provide significant advancements in answering important questions related to naturally occurring cancers.
Translational research: The journal welcomes translational research, which involves the application of basic scientific findings to human health and clinical practice.
Clinical investigations: Cancer Cell is interested in publishing clinical investigations that contribute to establishing new paradigms in the treatment, diagnosis, or prevention of cancers.
Insights into cancer biology: The journal values clinical investigations that provide important insights into cancer biology beyond what has been revealed by preclinical studies.
Mechanism-based proof-of-principle studies: Cancer Cell encourages the publication of mechanism-based proof-of-principle clinical studies, which demonstrate the feasibility of a specific therapeutic approach or diagnostic test.