Journal Article

Tumor-resident T cells and dendritic cells form an in situ archetype during immunotherapy response in melanoma

Schlenker, Ramona, Zhu, Ruiqing, Gyorki, David E, Chan, Joanna, McArthur, Grant A, Chalmers, Hugh, Neeson, Paul J, Levesque, Mitchell P, Crock, Patrick, Rao, Aparna D, Mackay, Laura K, Macdonald, Sean, Winch, Karen, Spain, Lavinia, Nguyen, Thu Ngoc, Di Pietro, Andrea, Sandhu, Shahneen, Bacac, Marina, Molden-Hauer, Tristan, Mailer, Sonia, Airaghi, Alessia, Yeung, George Au, Schwalie, Petra, Au, Lewis, Pizzolla, Angela, Barnes-Cullen, Kristy, Thio, Niko

2026

Overview

Tumor-resident (TR) T cells, known as tissue-resident memory (TRM) T cells in mice, play a central role in melanoma immunosurveillance, yet their contribution to immune checkpoint inhibitor (ICI) therapy has not been comprehensively explored. We performed spatial and single-cell profiling on 32 metastatic melanoma lymph node samples, from treatment-naïve, ICI-resistant and ICI-responsive patients. Here we show that tumor areas in ICI-responders were enriched for both CD8 and CD4 TR. CD8 TR cells were clonally expanded, and both CD8 and CD4 TR cells upregulated cytotoxicity-related gene expression, suggesting functional anti-tumor immunity. Conversely, ICI-resistant tumors displayed chronic IFN-γ response pathways, linked to T cell exhaustion. We further identified a spatially organized immune triad composed of CD8⁺ TR, CD4⁺ TR, and type-3 dendritic cells (DC3) that is exclusive to responding tumors. These findings define coordinated cellular interactions within the tumor microenvironment that underpin successful immunotherapy and provide a framework for spatial biomarkers of response.