CD103+CD8+ tissue‐resident memory T lymphocytes of melanoma boost anti‐tumour immunity and predict immunotherapy outcomes

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. CD103 + CD8 + TRM cells exhibit potent anti‐tumour immune activity. CD103 + CD8 + TRM cells predict favourable responses to immunotherapy in melanoma.