Distinct migratory dendritic cell subsets cooperate to prime tissue-resident memory-like CD8⁺ T cells in mouse tumors

Tumor-infiltrating tissue-resident memory (TRM)-like CD8+ T cells correlate with positive prognosis and better responses to cancer immunotherapy, yet the mechanisms underlying their specification remain ill-understood. Here, we use the KP (KrasG12D, p53-/-) mouse model of lung adenocarcinoma to investigate how different dendritic cell (DC) subsets shape tumor-specific CD8+ T cell responses. Selective ablation of XCR1+ DC1s or IRF4-dependent CD11b+ DC2s reveal that DC1s, but not DC2s, are required for the generation of tumor-infiltrating effector and exhausted CD8+ T cells. By contrast, both migratory DC1s and migratory DC2s contribute to the specification of CD103+CD69+ TRM-like CD8+ T cells in tumor-draining lymph nodes. Mechanistically, low peptide/MHC-I density on migratory DC2s favors TGFβ-dependent TRM differentiation, while high peptide/MHC-I density on DC1s promote proliferative expansion of TRM-like cells; in addition, IL-12 secreted by DC1s enhances CXCR6 expression. Together, our findings uncover complementary functions of migratory DC subsets in shaping anti-tumor TRM-like CD8+ T cell responses, and also implicate targeting multiple DC subsets for optimizing cancer immunotherapy. Tissue-resident memory (TRM) CD8+ T cells in the tumor microenvironment are relevant for anti-tumor immunity and immune checkpoint blockade response. Here, the authors conditionally ablate type 1 and type 2 dendritic cells in a lung cancer mouse model, finding both to be critical for the differentiation and expansion of TRM-like T cells.

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Journal
Nature Communications
Published
2026-09-18
DOI
https://doi.org/10.1038/s41467-026-77641-7
Primary Topic
Immunotherapy and Immune Responses
Type
article
Field-Weighted Citation Impact
0.00

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article

Distinct migratory dendritic cell subsets cooperate to prime tissue-resident memory-like CD8⁺ T cells in mouse tumors

Massimiliano Mazzone, Kairbaan Hodivala‐Dilke, Emmanuel L. Gautier, Roberto Savoldelli et al.
Nature Communications
Immunotherapy and Immune Responses
article

Distinct migratory dendritic cell subsets cooperate to prime tissue-resident memory-like CD8⁺ T cells in mouse tumors

Massimiliano Mazzone, Kairbaan Hodivala‐Dilke, Emmanuel L. Gautier, Roberto Savoldelli, Éric Tartour, Julie Helft, Marc Dalod, Yohan Gerber-Ferder, Zacarias Garcia, Camille Blériot, Yosuke Kumamoto, Klaas P. J. M. van Gisbergen, Pierre Bourdely, Florent Ginhoux, Pierre Guermonprez, Mathias Vétillard, Nathan Vaudiau, Loredana Saveanu, Tessa Bergsbaken, Abdenour Abbas, Guillaume Darrasse-Jèze, Federica Benvenuti, Maria Semitekolou, Fillipe Luiz Rosa Do Carmo, Amady Coulibaly, Judith Weber, Audrey Rood, Syrine Bouallègue, Konstantina Pamboukas, Agathe Ok, Louise Gorline, Aurélie Semervil, Jérémie Bornères, Matthieu Rastello, Philippe Bousso, Marie Guillin
article en

Abstract

Tumor-infiltrating tissue-resident memory (TRM)-like CD8+ T cells correlate with positive prognosis and better responses to cancer immunotherapy, yet the mechanisms underlying their specification remain ill-understood. Here, we use the KP (KrasG12D, p53-/-) mouse model of lung adenocarcinoma to investigate how different dendritic cell (DC) subsets shape tumor-specific CD8+ T cell responses. Selective ablation of XCR1+ DC1s or IRF4-dependent CD11b+ DC2s reveal that DC1s, but not DC2s, are required for the generation of tumor-infiltrating effector and exhausted CD8+ T cells. By contrast, both migratory DC1s and migratory DC2s contribute to the specification of CD103+CD69+ TRM-like CD8+ T cells in tumor-draining lymph nodes. Mechanistically, low peptide/MHC-I density on migratory DC2s favors TGFβ-dependent TRM differentiation, while high peptide/MHC-I density on DC1s promote proliferative expansion of TRM-like cells; in addition, IL-12 secreted by DC1s enhances CXCR6 expression. Together, our findings uncover complementary functions of migratory DC subsets in shaping anti-tumor TRM-like CD8+ T cell responses, and also implicate targeting multiple DC subsets for optimizing cancer immunotherapy. Tissue-resident memory (TRM) CD8+ T cells in the tumor microenvironment are relevant for anti-tumor immunity and immune checkpoint blockade response. Here, the authors conditionally ablate type 1 and type 2 dendritic cells in a lung cancer mouse model, finding both to be critical for the differentiation and expansion of TRM-like T cells.

Nature Communications
Rutgers, The State University of New Jersey (US), Champalimaud Foundation (PT), Agency for Science, Technology and Research (SG), Centre National de la Recherche Scientifique (FR), Inserm (FR), Institut Pasteur (FR), Queen Mary University of London (GB), Université Paris Cité (FR), Université Paris-Saclay (FR), Singapore Immunology Network (SG), Institut Gustave Roussy (FR), Foundation for Liver Research (GB), Sorbonne Université (FR), VIB-KU Leuven Center for Cancer Biology (BE), Nutrition et obésité : approches systémiques (FR), Centre d'Immunologie et des Maladies Infectieuses (FR), Centre de Recherche sur l'Inflammation (FR), Paris Cardiovascular Research Center (FR), Institut Cochin (FR), Centre d’Immunologie de Marseille-Luminy (FR), Rutgers New Jersey Medical School (US), International Centre for Genetic Engineering and Biotechnology (IT)
Cancer Research UK, Fondation ARC pour la Recherche sur le Cancer
Good health and well-being
Openalex Percentile: Top 17%
Immunotherapy and Immune Responses
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