Dendritic cells control tertiary lymphoid structure development and maintenance in cancer
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.
Article Details
Journal Info
Science
American Association for the Advancement of Science
Authors (68)
Raphaël Mattiuz
Jesse Boumelha
Emmanouil Aerakis
Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Jessica Le Berichel
Pauline Hamon
Laszlo Halasz
Abishek Vaidya
Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Brian Y. Soong
Emir Radkevich
Hye Mi Kim
Tumor Microenvironment Center, Department of Immunology, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, USA.
Matthew D. Park
Romain Donne
Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Leanna Troncoso
Rachel A. Kaplan
Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Clotilde Hennequin
Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Isaias Hernández-Verdin
Department of Immunology, Inflammation, Complement and Cancer, Centre de Recherche des Cordeliers, Sorbonne Université, INSERM, Université Paris Cité, Paris, France.
Lucía López
Cellular Immunology, International Centre for Genetic Engineering and Biotechnology, ICGEB, Trieste, Italy.
Frederika Rentzeperis
Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Darwin D’Souza
Medard Ernest Kaiza
Tumor Microenvironment Center, Department of Immunology, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, USA.
Ian P. MacFawn
Tumor Microenvironment Center, Department of Immunology, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, USA.
Meriem Belabed
Guillaume Mestrallet
Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Etienne Humblin
Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Raphaël Merand
Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Samarth Hegde
Jean-Christophe Lone
GIMM, Gulbenkian Institute for Molecular Medicine and Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal.
Giorgio Ioannou
Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Sinem Ozbey
Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Igor Figueiredo
Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Alexander Tepper
Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Hajer Merarda
Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Nadine Serhan
Maximilian M. Schaefer
Jinping An
Howard Hughes Medical Institute and Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA, USA.
Ray A. Ohara
Erika Nemeth
Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Simon Goldstein
Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Amanda M. Reid
Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Moataz Noureddine
Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Alexandra Tabachnikova
Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Giulia Maria Piperno
Cellular Immunology, International Centre for Genetic Engineering and Biotechnology, ICGEB, Trieste, Italy.
Maria Tsoumakidou
Institute for Bioinnovation, “Alexander Fleming” Biomedical Sciences Research Center, Vari, Greece.
Jalal Ahmed
Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Alexandros D. Polydorides
Henry D. Janowitz Division of Gastroenterology, Department of Medicine, and Department of Pathology, Molecular and Cell-Based Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Nina Bhardwaj
Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Amaia Lujambio
Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Zhihong Chen
Edgar Gonzalez Kozlova
Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Seunghee Kim-Schulze
Joshua D. Brody
Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Michael Schotsaert
Christine Moussion
Genentech, South San Francisco, CA, USA.
Sacha Gnjatic
Vladimir Roudko
Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Florent Ginhoux
Kenneth M. Murphy
Catherine Sautès-Fridman
Department of Immunology, Inflammation, Complement and Cancer, Centre de Recherche des Cordeliers, Sorbonne Université, INSERM, Université Paris Cité, Paris, France.
Wolf Herman Fridman
Department of Immunology, Inflammation, Complement and Cancer, Centre de Recherche des Cordeliers, Sorbonne Université, INSERM, Université Paris Cité, Paris, France.
Brian D. Brown
Thomas U. Marron
Federica Benvenuti
Cellular Immunology, International Centre for Genetic Engineering and Biotechnology, ICGEB, Trieste, Italy.
Jason G. Cyster
Hélène Salmon
Institut Curie, Paris, France.
Tullia C. Bruno
Tumor Microenvironment Center, Department of Immunology, UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, USA.
Nikhil S. Joshi
Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA.
Alice O. Kamphorst
Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Miriam Merad