{"title":"CD103+CD8+ tissue-resident memory T lymphocytes of melanoma boost anti-tumour immunity and predict immunotherapy outcomes","authors":"Tianyi Zhang, Junquan Song, Yinlam Li, Kangjie Shen, Jiangying Xuan, Yuan Gao, Lili Lu, Zhi Pang, Lu Wang, Yang Yang, Zixu Gao, Qianrong Hu, Yu Zhu, Chenlu Wei, Shaoluan Zheng, Rongkui Luo, Yingyong Hou, Yuhong Zhou, Chuanyuan Wei, Jianying Gu","doi":"10.1002/ctm2.70464","DOIUrl":null,"url":null,"abstract":"<div>\n \n \n <section>\n \n <h3> Background</h3>\n \n <p>Immunotherapy has revolutionised melanoma treatment, providing significant clinical benefits by reactivating the anti-tumour immune system. CD8<sup>+</sup> tissue-resident memory T lymphocytes (CD8<sup>+</sup> TRM) have emerged as crucial mediators of anti-tumour immunity, while their specific role in melanoma remains poorly understood.</p>\n </section>\n \n <section>\n \n <h3> Methods</h3>\n \n <p>Following CD8<sup>+</sup>CD45.1<sup>+</sup> OT-1 cell adoptive transfer into CD45.2<sup>+</sup> mice, we employed magnetic separation to purify and analyse resident memory CD8<sup>+</sup> T cells (TRM). We use multiple immunohistochemistry (mIHC) to evaluate the spatial distribution of CD8<sup>+</sup> TRM in ZS melanoma cohort. Additionally, the biological function of CD8<sup>+</sup> TRM and their impact on anti-tumour immunity are explored using scRNA sequencing and spatial transcriptomics, coupled with in vivo/in vitro experiments. Finally, CD8<sup>+</sup> TRM utility as an immunotherapy response predictor is examined across several independent cohorts.</p>\n </section>\n \n <section>\n \n <h3> Results</h3>\n \n <p>CD8<sup>+</sup> TRM demonstrates potent tumour-killing capabilities in melanoma, with CD103 as a distinctive marker. High CD103<sup>+</sup>CD8<sup>+</sup> TRM infiltration in tumour tissues strongly correlates with improved prognosis in melanoma patients. In vivo adoptive transfer of CD103<sup>+</sup>CD8<sup>+</sup> TRM effectively inhibits melanoma progression. Mechanistically, CD103 activates the integrin-dependent PI3K/AKT signalling cascade, promoting both proliferation and anti-tumour effector functions of CD8<sup>+</sup> TRM. Notably, CD103<sup>+</sup>CD8<sup>+</sup> TRM preferentially localises within tertiary lymphoid structures (TLS), and its adoptive transfer promotes TLS formation. Clinically, CD103<sup>+</sup>CD8<sup>+</sup> TRM is enriched in immunotherapy-responsive patients and serves as a strong predictor for immune checkpoint blockade (ICB) treatment outcomes.</p>\n </section>\n \n <section>\n \n <h3> Conclusions</h3>\n \n <p>CD103<sup>+</sup> CD8<sup>+</sup> TRM cells in melanoma play a key role in the anti-tumour immune process and can also be used as a reliable predictor of immunotherapy efficacy.</p>\n </section>\n \n <section>\n \n <h3> Key points</h3>\n \n <div>\n <ul>\n \n <li>\n <p>CD103 is a reliable marker of tissue-resident memory (TRM) CD8<sup>+</sup> T cells in melanoma.</p>\n </li>\n \n <li>\n <p>CD103<sup>+</sup>CD8<sup>+</sup> TRM cells exhibit potent anti-tumour immune activity.</p>\n </li>\n \n <li>\n <p>CD103<sup>+</sup>CD8<sup>+</sup> TRM cells predict favourable responses to immunotherapy in melanoma.</p>\n </li>\n </ul>\n </div>\n </section>\n </div>","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"15 9","pages":""},"PeriodicalIF":6.8000,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12456097/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Clinical and Translational Medicine","FirstCategoryId":"3","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1002/ctm2.70464","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"MEDICINE, RESEARCH & EXPERIMENTAL","Score":null,"Total":0}
引用次数: 0
Abstract
Background
Immunotherapy has revolutionised melanoma treatment, providing significant clinical benefits by reactivating the anti-tumour immune system. CD8+ tissue-resident memory T lymphocytes (CD8+ TRM) have emerged as crucial mediators of anti-tumour immunity, while their specific role in melanoma remains poorly understood.
Methods
Following CD8+CD45.1+ OT-1 cell adoptive transfer into CD45.2+ mice, we employed magnetic separation to purify and analyse resident memory CD8+ T cells (TRM). We use multiple immunohistochemistry (mIHC) to evaluate the spatial distribution of CD8+ TRM in ZS melanoma cohort. Additionally, the biological function of CD8+ TRM and their impact on anti-tumour immunity are explored using scRNA sequencing and spatial transcriptomics, coupled with in vivo/in vitro experiments. Finally, CD8+ TRM utility as an immunotherapy response predictor is examined across several independent cohorts.
Results
CD8+ TRM demonstrates potent tumour-killing capabilities in melanoma, with CD103 as a distinctive marker. High CD103+CD8+ TRM infiltration in tumour tissues strongly correlates with improved prognosis in melanoma patients. In vivo adoptive transfer of CD103+CD8+ TRM effectively inhibits melanoma progression. Mechanistically, CD103 activates the integrin-dependent PI3K/AKT signalling cascade, promoting both proliferation and anti-tumour effector functions of CD8+ TRM. Notably, CD103+CD8+ TRM preferentially localises within tertiary lymphoid structures (TLS), and its adoptive transfer promotes TLS formation. Clinically, CD103+CD8+ TRM is enriched in immunotherapy-responsive patients and serves as a strong predictor for immune checkpoint blockade (ICB) treatment outcomes.
Conclusions
CD103+ CD8+ TRM cells in melanoma play a key role in the anti-tumour immune process and can also be used as a reliable predictor of immunotherapy efficacy.
Key points
CD103 is a reliable marker of tissue-resident memory (TRM) CD8+ T cells in melanoma.
期刊介绍:
Clinical and Translational Medicine (CTM) is an international, peer-reviewed, open-access journal dedicated to accelerating the translation of preclinical research into clinical applications and fostering communication between basic and clinical scientists. It highlights the clinical potential and application of various fields including biotechnologies, biomaterials, bioengineering, biomarkers, molecular medicine, omics science, bioinformatics, immunology, molecular imaging, drug discovery, regulation, and health policy. With a focus on the bench-to-bedside approach, CTM prioritizes studies and clinical observations that generate hypotheses relevant to patients and diseases, guiding investigations in cellular and molecular medicine. The journal encourages submissions from clinicians, researchers, policymakers, and industry professionals.