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.

Keywords

immunotherapy / melanoma / TIL / tissue-resident memory T lymphocytes

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2025 The Author(s). Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.