Tong Fu, Xi Jin, Min He, Yi-Yu Chen, Yun-Song Yang, Li Chen, Hu-Yun-Long Zhang, Lei Fan, Jiong Wu, Zhong-Hua Wang, Yi-Wei Chu, Rong-Hua Liu, Yi-Zhou Jiang, Zhi-Ming Shao
{"title":"干扰素诱导的衰老CD8+ T细胞降低抗pd1免疫治疗早期三阴性乳腺癌的疗效","authors":"Tong Fu, Xi Jin, Min He, Yi-Yu Chen, Yun-Song Yang, Li Chen, Hu-Yun-Long Zhang, Lei Fan, Jiong Wu, Zhong-Hua Wang, Yi-Wei Chu, Rong-Hua Liu, Yi-Zhou Jiang, Zhi-Ming Shao","doi":"10.1126/scitranslmed.adj7808","DOIUrl":null,"url":null,"abstract":"<div >Triple-negative breast cancers (TNBCs) lack predictive biomarkers to guide immunotherapy, especially during early-stage disease. To address this issue, we used single-cell RNA sequencing, bulk transcriptomics, and pathology assays on samples from 171 patients with early-stage TNBC receiving chemotherapy with or without immunotherapy. Our investigation identified an enriched subset of interferon (IFN)–induced CD8<sup>+</sup> T cells in early TNBC samples, which predict immunotherapy nonresponsiveness. Mechanistically, IFN produced by HLA-DR<sup>+</sup> monocytes triggered cellular senescence in CD8<sup>+</sup> T cells, which was marked by excessive NAD<sup>+</sup> consumption, reduced cytotoxicity, and immunotherapy nonresponsiveness. Nicotinamide mononucleotide treatment restored the function of IFN-induced senescent CD8<sup>+</sup> T cells and enhanced immunotherapy efficacy in patient-derived organoid–T cell coculture and in mouse models. Overall, our study identifies IFN-induced T cell senescence as a driver of immunotherapy nonresponsiveness in early TNBC and provides a strategy to restore CD8<sup>+</sup> T cell function for immunotherapeutic benefit.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 815","pages":""},"PeriodicalIF":14.6000,"publicationDate":"2025-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Interferon-induced senescent CD8+ T cells reduce anti-PD1 immunotherapy efficacy in early triple-negative breast cancer\",\"authors\":\"Tong Fu, Xi Jin, Min He, Yi-Yu Chen, Yun-Song Yang, Li Chen, Hu-Yun-Long Zhang, Lei Fan, Jiong Wu, Zhong-Hua Wang, Yi-Wei Chu, Rong-Hua Liu, Yi-Zhou Jiang, Zhi-Ming Shao\",\"doi\":\"10.1126/scitranslmed.adj7808\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div >Triple-negative breast cancers (TNBCs) lack predictive biomarkers to guide immunotherapy, especially during early-stage disease. To address this issue, we used single-cell RNA sequencing, bulk transcriptomics, and pathology assays on samples from 171 patients with early-stage TNBC receiving chemotherapy with or without immunotherapy. Our investigation identified an enriched subset of interferon (IFN)–induced CD8<sup>+</sup> T cells in early TNBC samples, which predict immunotherapy nonresponsiveness. Mechanistically, IFN produced by HLA-DR<sup>+</sup> monocytes triggered cellular senescence in CD8<sup>+</sup> T cells, which was marked by excessive NAD<sup>+</sup> consumption, reduced cytotoxicity, and immunotherapy nonresponsiveness. Nicotinamide mononucleotide treatment restored the function of IFN-induced senescent CD8<sup>+</sup> T cells and enhanced immunotherapy efficacy in patient-derived organoid–T cell coculture and in mouse models. Overall, our study identifies IFN-induced T cell senescence as a driver of immunotherapy nonresponsiveness in early TNBC and provides a strategy to restore CD8<sup>+</sup> T cell function for immunotherapeutic benefit.</div>\",\"PeriodicalId\":21580,\"journal\":{\"name\":\"Science Translational Medicine\",\"volume\":\"17 815\",\"pages\":\"\"},\"PeriodicalIF\":14.6000,\"publicationDate\":\"2025-09-10\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Science Translational Medicine\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.science.org/doi/10.1126/scitranslmed.adj7808\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"CELL BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Science Translational Medicine","FirstCategoryId":"3","ListUrlMain":"https://www.science.org/doi/10.1126/scitranslmed.adj7808","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CELL BIOLOGY","Score":null,"Total":0}
Interferon-induced senescent CD8+ T cells reduce anti-PD1 immunotherapy efficacy in early triple-negative breast cancer
Triple-negative breast cancers (TNBCs) lack predictive biomarkers to guide immunotherapy, especially during early-stage disease. To address this issue, we used single-cell RNA sequencing, bulk transcriptomics, and pathology assays on samples from 171 patients with early-stage TNBC receiving chemotherapy with or without immunotherapy. Our investigation identified an enriched subset of interferon (IFN)–induced CD8+ T cells in early TNBC samples, which predict immunotherapy nonresponsiveness. Mechanistically, IFN produced by HLA-DR+ monocytes triggered cellular senescence in CD8+ T cells, which was marked by excessive NAD+ consumption, reduced cytotoxicity, and immunotherapy nonresponsiveness. Nicotinamide mononucleotide treatment restored the function of IFN-induced senescent CD8+ T cells and enhanced immunotherapy efficacy in patient-derived organoid–T cell coculture and in mouse models. Overall, our study identifies IFN-induced T cell senescence as a driver of immunotherapy nonresponsiveness in early TNBC and provides a strategy to restore CD8+ T cell function for immunotherapeutic benefit.
期刊介绍:
Science Translational Medicine is an online journal that focuses on publishing research at the intersection of science, engineering, and medicine. The goal of the journal is to promote human health by providing a platform for researchers from various disciplines to communicate their latest advancements in biomedical, translational, and clinical research.
The journal aims to address the slow translation of scientific knowledge into effective treatments and health measures. It publishes articles that fill the knowledge gaps between preclinical research and medical applications, with a focus on accelerating the translation of knowledge into new ways of preventing, diagnosing, and treating human diseases.
The scope of Science Translational Medicine includes various areas such as cardiovascular disease, immunology/vaccines, metabolism/diabetes/obesity, neuroscience/neurology/psychiatry, cancer, infectious diseases, policy, behavior, bioengineering, chemical genomics/drug discovery, imaging, applied physical sciences, medical nanotechnology, drug delivery, biomarkers, gene therapy/regenerative medicine, toxicology and pharmacokinetics, data mining, cell culture, animal and human studies, medical informatics, and other interdisciplinary approaches to medicine.
The target audience of the journal includes researchers and management in academia, government, and the biotechnology and pharmaceutical industries. It is also relevant to physician scientists, regulators, policy makers, investors, business developers, and funding agencies.