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

di Pietro, A; Au, L; Crock, P; Thio, N; Pizzolla, A; Nguyen, TN; Macdonald, S; Chalmers, H; Zhu, R; Airaghi, A; Molden-Hauer, T; Bacac, M; Schwalie, P; Schlenker, R; Levesque, MP; Mailer, S; Barnes-Cullen, K; Winch, K; Chan, J; Yeung, GA; Spain, L; Rao, AD; Sandhu, S; Gyorki, DE; McArthur, GA; Mackay, LK; Neeson, PJ

Author(s): di Pietro, A; Au, L; Crock, P; Thio, N; Pizzolla, A; Nguyen, TN; Macdonald, S; Chalmers, H; Zhu, R; Airaghi, A; Molden-Hauer, T; Bacac, M; Schwalie, P; Schlenker, R; Levesque, MP; Mailer, S; Barnes-Cullen, K; Winch, K; Chan, J; Yeung, GA; Spain, L; Rao, AD; Sandhu, S; Gyorki, DE; McArthur, GA; Mackay, LK; Neeson, PJ;
Details: Publication Year 2026-06-11,Volume 17,Issue #1,Page 7445
Journal Title: Nature Communications
Publication Type: Research article
Abstract: 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.
Publisher: Springer Nature
Department(s): Laboratory Research; Medical Oncology; Surgical Oncology
Publisher's Version: https://doi.org/10.1038/s41467-026-74076-y
Open Access at Publisher's Site: https://doi.org/10.1038/s41467-026-74076-y
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2026-06-25 06:02:48

Last Modified: 2026-08-11 02:01:22