Tumor-resident T cells and dendritic cells form an in situ archetype for immunotherapy response in melanoma [scRNA-seq]

Tumor-resident (TR) T cells participate in immunosurveillance of melanoma, but their role in determining response to immune checkpoint inhibitors (ICI) has not been comprehensively explored. We performed spatial and single-cell profiling on 32 metastatic melanoma lymph node samples, from treatment-naïve, ICI-resistant, or ICI-responsive patients. In responders, we found enrichment for early differentiation (TCF1+) CD8+ and CD4+ TR which co-localized with melanoma cells. CD8+ TR were hyperexpanded, and both CD8+ and CD4+ TR upregulated cytotoxicity-related gene expression, suggesting functional anti-tumor immunity. Conversely, ICI-resistant tumors displayed chronic IFN-γ responses within the tumor microenvironment to potentiate T cell exhaustion. In ICI-responsive melanoma tumors, CD8⁺ TR interact with CD4⁺ TR cells (via the CCL4-CCR5 axis) and engage with type-3 dendritic cells (DC3) (via IL15-IL15R interaction). This intratumoral immune triad (CD8⁺ TR – CD4⁺ TR – DC) is exclusive to responders. This study illustrates the role of TR cells and their crosstalk with DCs in effective ICI responses.