CD103(+)CD8(+) tissue-resident memory T lymphocytes of melanoma boost anti-tumour immunity and predict immunotherapy outcomes.

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.