Dendritic cells control tertiary lymphoid structure development and maintenance in cancer

Tertiary lymphoid structures (TLSs) are associated with immunotherapy response, yet the mechanisms controlling their formation and maintenance remain unclear. Using spatial transcriptomics and multiplex imaging across human tumors, we found that CCR7 + mature dendritic cells (DCs) accumulate in TLSs. In a mouse non–small cell lung cancer model that forms mature TLSs, we show that early TLS development requires interferon-γ (IFN-γ)–driven type 1 conventional dendritic cell (cDC1) maturation, migration to tumor-draining lymph nodes (tdLNs), and T cell recruitment. As tumors progress, TLSs persist independently of tdLN T cell egress, coinciding with cDC1 accumulation within intratumoral CCL19 stromal hubs. There, cDC1–major histocompatibility complex class 1 (MHC-I) and –MHC-II concomitant antigen presentation, along with CD40 signaling, sustain TLS, T follicular helper (T FH ) cell pool, germinal centers, and tumor-specific immunoglobulin G (IgG). These findings highlight local mature cDC1s as key TLS orchestrators and potential targets to enhance antitumor TLS function.

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Publication Details

Journal
Science
Published
2026-07-16
DOI
https://doi.org/10.1126/science.ady1678
Citations
1
Primary Topic
Immunotherapy and Immune Responses
Type
article
Field-Weighted Citation Impact
4.40

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Dendritic cells control tertiary lymphoid structure development and maintenance in cancer

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Dendritic cells control tertiary lymphoid structure development and maintenance in cancer

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article en
1 citations

Abstract

Tertiary lymphoid structures (TLSs) are associated with immunotherapy response, yet the mechanisms controlling their formation and maintenance remain unclear. Using spatial transcriptomics and multiplex imaging across human tumors, we found that CCR7 + mature dendritic cells (DCs) accumulate in TLSs. In a mouse non–small cell lung cancer model that forms mature TLSs, we show that early TLS development requires interferon-γ (IFN-γ)–driven type 1 conventional dendritic cell (cDC1) maturation, migration to tumor-draining lymph nodes (tdLNs), and T cell recruitment. As tumors progress, TLSs persist independently of tdLN T cell egress, coinciding with cDC1 accumulation within intratumoral CCL19 stromal hubs. There, cDC1–major histocompatibility complex class 1 (MHC-I) and –MHC-II concomitant antigen presentation, along with CD40 signaling, sustain TLS, T follicular helper (T FH ) cell pool, germinal centers, and tumor-specific immunoglobulin G (IgG). These findings highlight local mature cDC1s as key TLS orchestrators and potential targets to enhance antitumor TLS function.

ScienceVol. 393(6808)
Howard Hughes Medical Institute (US), University of Lisbon (PT), Inserm (FR), University of California, San Francisco (US), Grove City College (US), Washington University in St. Louis (US), Université Paris Cité (FR), Université Paris-Saclay (FR), Institut Gustave Roussy (FR), Yale University (US), Sorbonne Université (FR), Centre de Recherche des Cordeliers (FR), UPMC Hillman Cancer Center (US), Alexander Fleming Biomedical Sciences Research Center (GR), Institut Curie (FR), International Centre for Genetic Engineering and Biotechnology (IT), Icahn School of Medicine at Mount Sinai (US)
American Association for Cancer Research, Cancer Research Institute, American Federation for Aging Research, Boehringer Ingelheim, Damon Runyon Cancer Research Foundation, Bodossaki Foundation, National Institutes of Health, European Research Council, National Cancer Institute
Openalex Percentile: Top 4%
Immunotherapy and Immune Responses
4.40
DOISourceOpenAlex
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