Positioning and reversible suppression of CCR7+ dendritic cells in perivascular tumor niches shape cancer immunity

Article Article scientifique Article Positioning and reversible suppression of CCR7+ dendritic cells in perivascular tumor niches shape cancer immunity eng 2025-12-19 2026-01-13 author Zitti Béatrice 0000-0003-4610-7535 Department of Pathology and Immunology, and Center for Translational Oncohaematology Research, University of Geneva, Geneva, Switzerland; AGORA Cancer Research Center, and Swiss Cancer Center Leman, Lausanne, Switzerland. 973448 author Duval Florent 0000-0002-3652-184X Department of Pathology and Immunology, and Center for Translational Oncohaematology Research, University of Geneva, Geneva, Switzerland; AGORA Cancer Research Center, and Swiss Cancer Center Leman, Lausanne, Switzerland. 968529 Département de pathologie et immunologie (PATIM) author Wirapati Pratyaksha Department of Pathology and Immunology, and Center for Translational Oncohaematology Research, University of Geneva, Geneva, Switzerland; AGORA Cancer Research Center, and Swiss Cancer Center Leman, Lausanne, Switzerland. 982767 author Hicham Mehdi Department of Pathology and Immunology, and Center for Translational Oncohaematology Research, University of Geneva, Geneva, Switzerland; AGORA Cancer Research Center, and Swiss Cancer Center Leman, Lausanne, Switzerland. 402634 Département de pathologie et immunologie (PATIM) author Xie Yuxuan Department of Pathology and Immunology, and Center for Translational Oncohaematology Research, University of Geneva, Geneva, Switzerland; AGORA Cancer Research Center, and Swiss Cancer Center Leman, Lausanne, Switzerland. 413030 Département de pathologie et immunologie (PATIM) author Oh Juhyun Center for Systems Biology, Massachusetts General Brigham and Harvard Medical School, Boston, MA, USA. author Hoelzl Jan Center for Systems Biology, Massachusetts General Brigham and Harvard Medical School, Boston, MA, USA; Department of Medical Oncology, Heidelberg University Hospital, Heidelberg, Germany. author Meiser Philippa 0009-0007-9334-1072 Institute of Molecular Immunology, TUM University Hospital, School of Medicine and Health, Technical University of Munich (TUM), Munich, Germany. author Varrone Marco AGORA Cancer Research Center, and Swiss Cancer Center Leman, Lausanne, Switzerland; Department of Computational Biology, University of Lausanne, Lausanne, Switzerland; Swiss Institute of Bioinformatics, Lausanne, Switzerland. author Peterson Hannah M Center for Systems Biology, Massachusetts General Brigham and Harvard Medical School, Boston, MA, USA. author Cianciaruso Chiara Department of Pathology and Immunology, and Center for Translational Oncohaematology Research, University of Geneva, Geneva, Switzerland; AGORA Cancer Research Center, and Swiss Cancer Center Leman, Lausanne, Switzerland. 936265 author Bill Ruben 0000-0002-4674-2531 Department of Pathology and Immunology, and Center for Translational Oncohaematology Research, University of Geneva, Geneva, Switzerland; AGORA Cancer Research Center, and Swiss Cancer Center Leman, Lausanne, Switzerland. 974134 author Bayerl Félix 0000-0002-4737-1808 Department of Pathology and Immunology, and Center for Translational Oncohaematology Research, University of Geneva, Geneva, Switzerland; AGORA Cancer Research Center, and Swiss Cancer Center Leman, Lausanne, Switzerland. 416933 Département de pathologie et immunologie (PATIM) author Bolli Evangelia Department of Pathology and Immunology, and Center for Translational Oncohaematology Research, University of Geneva, Geneva, Switzerland; AGORA Cancer Research Center, and Swiss Cancer Center Leman, Lausanne, Switzerland. 941512 author Goubet Anne-Gaëlle Department of Pathology and Immunology, and Center for Translational Oncohaematology Research, University of Geneva, Geneva, Switzerland; AGORA Cancer Research Center, and Swiss Cancer Center Leman, Lausanne, Switzerland. 975976 Département de pathologie et immunologie (PATIM) author Kiss Mate Department of Pathology and Immunology, and Center for Translational Oncohaematology Research, University of Geneva, Geneva, Switzerland; AGORA Cancer Research Center, and Swiss Cancer Center Leman, Lausanne, Switzerland. 950431 author Mcdowell Sheri 0000-0002-3155-8547 Department of Pathology and Immunology, and Center for Translational Oncohaematology Research, University of Geneva, Geneva, Switzerland; AGORA Cancer Research Center, and Swiss Cancer Center Leman, Lausanne, Switzerland. 406034 Département de pathologie et immunologie (PATIM) author Cheng Phil 0000-0003-2940-006X AGORA Cancer Research Center, and Swiss Cancer Center Leman, Lausanne, Switzerland; Department of Oncology, Geneva University Hospital, Geneva, Switzerland. 418075 author Celestini Dan AGORA Cancer Research Center, and Swiss Cancer Center Leman, Lausanne, Switzerland; Department of Oncology, Geneva University Hospital, Geneva, Switzerland. 990264 centres facultaires de la faculté de médecine (CTRFM) author Terzic Julie Department of Pathology and Immunology, and Center for Translational Oncohaematology Research, University of Geneva, Geneva, Switzerland; AGORA Cancer Research Center, and Swiss Cancer Center Leman, Lausanne, Switzerland. 990178 Département de pathologie et immunologie (PATIM) author Zwahlen Thomas Department of Pathology and Immunology, and Center for Translational Oncohaematology Research, University of Geneva, Geneva, Switzerland; AGORA Cancer Research Center, and Swiss Cancer Center Leman, Lausanne, Switzerland. 424652 author Alouche Nagham Department of Immunobiology, University of Lausanne, Lausanne, Switzerland. author Zouggari Nawel Department of Oncology, Geneva University Hospital, Geneva, Switzerland. 832877 author Tarussio David Department of Oncology, Center for Experimental Therapeutics, Lausanne University Hospital (CHUV), Lausanne, Switzerland. author Tissot Stephanie Department of Oncology, Center for Experimental Therapeutics, Lausanne University Hospital (CHUV), Lausanne, Switzerland. author Nunes-Hasler Paula 0000-0002-4598-685X Department of Pathology and Immunology, and Center for Translational Oncohaematology Research, University of Geneva, Geneva, Switzerland. 707324 Département de pathologie et immunologie (PATIM) author Mino-Kenudson Mari Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. author Lanuti Michael Division of Thoracic Surgery, Massachusetts General Hospital, Boston, MA, USA. author Faquin William C Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; Department of Otolaryngology, Massachusetts Eye and Ear, Harvard Medical School, Boston, MA, USA. author Sadow Peter M Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; Department of Otolaryngology, Massachusetts Eye and Ear, Harvard Medical School, Boston, MA, USA. author Tille Jean-Christophe Division of Clinical Pathology, Geneva University Hospitals, Geneva, Switzerland. 87627 author Labidi-Galy Sana Intidhar 0000-0002-0824-3475 Department of Oncology, Geneva University Hospital, Geneva, Switzerland. 817058 Département de médecine (DEMED) author Garris Christopher S Center for Systems Biology, Massachusetts General Brigham and Harvard Medical School, Boston, MA, USA; Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. author Hugues Stéphanie Department of Pathology and Immunology, and Center for Translational Oncohaematology Research, University of Geneva, Geneva, Switzerland. 663452 Département de pathologie et immunologie (PATIM) author Petrova Tatiana V Department of Oncology, University of Lausanne, Lausanne, Switzerland; Ludwig Institute for Cancer Research, Lausanne, Switzerland. author Ludewig Burkhard Institute of Immunobiology, Cantonal Hospital, St. Gallen, Switzerland; University Heart Center, University Hospital Zurich, Zurich, Switzerland; Center for Translational and Experimental Cardiology, University Hospital Zurich, Zurich, Switzerland. author Quezada Sergio Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK. author Luther Sanjiv Department of Immunobiology, University of Lausanne, Lausanne, Switzerland. author Mempel Thorsten R Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Boston, MA, USA. author Ciriello Giovanni AGORA Cancer Research Center, and Swiss Cancer Center Leman, Lausanne, Switzerland; Department of Computational Biology, University of Lausanne, Lausanne, Switzerland; Swiss Institute of Bioinformatics, Lausanne, Switzerland. author Pai Sara I Department of Surgery, Yale University School of Medicine, New Haven, CT, USA. author Michielin Olivier 0000-0003-4926-6355 AGORA Cancer Research Center, and Swiss Cancer Center Leman, Lausanne, Switzerland; Swiss Institute of Bioinformatics, Lausanne, Switzerland; Department of Oncology, Geneva University Hospital, Geneva, Switzerland. 903944 Département de médecine (DEMED) author Böttcher Jan P Institute of Molecular Immunology, TUM University Hospital, School of Medicine and Health, Technical University of Munich (TUM), Munich, Germany; Department of Experimental Immunology, Institute of Immunology, University of Tübingen, Tübingen, Germany; M3 Research Center, University Hospital Tübingen, University of Tübingen, Tübingen, Germany. author Weissleder Ralph Center for Systems Biology, Massachusetts General Brigham and Harvard Medical School, Boston, MA, USA; Department of Systems Biology, Harvard Medical School, Boston, MA, USA; Department of Radiology, Massachusetts General Hospital, and Harvard Medical School, Boston, MA, USA. author Pittet Mikaël 0000-0002-2060-4691 Department of Pathology and Immunology, and Center for Translational Oncohaematology Research, University of Geneva, Geneva, Switzerland; AGORA Cancer Research Center, and Swiss Cancer Center Leman, Lausanne, Switzerland; Department of Oncology, Geneva University Hospital, Geneva, Switzerland; Ludwig Institute for Cancer Research, Lausanne, Switzerland. Electronic address: mikael.pittet@unige.ch. 917678 Département de pathologie et immunologie (PATIM) 161-176.e12 10.1016/j.immuni.2025.11.020 41421339 1074-7613 PMC12882814 Tumor-resident CCR7+ dendritic cells (DCs) are key determinants of antitumor T cell responses. Here, we examined the localization of CCR7+ DCs within tumors and the impact of this positioning on antitumor immunity. Spatial, single-cell, and intravital analyses of human cancers and mouse models reveal that CCR7+ DCs form perivascular clusters. Fibroblasts surrounding venous blood vessels produced CCL19, guiding CCR7+ DCs into perivascular niches. Regulatory T (Treg) cells frequently contact perivascular CCR7+ DCs, suppressing CD40 expression and CD4+ and CD8+ T cell activation. Treg cell depletion restored CD40 expression by CCR7+ DCs, enhanced immunostimulatory programs, and improved T cell-dependent tumor control. Anti-PD-1 not only increased perivascular CCR7+ DC clustering and IL-12 production but also strengthened Treg-DC interactions through a CCL22-dependent mechanism, limiting therapeutic efficacy. CCR7+ DCs expressed both co-stimulatory and co-inhibitory molecules, which may underlie their capacity for antitumor activation and concurrent vulnerability to suppression. Modulating the mechanisms that form and restrain CCR7+ DC perivascular immune hubs may improve cancer immunotherapy. T cells Cancer immunity Cancer immunity cycle Chemokines Dendritic cells Immunotherapy Regulatory Dendritic Cells / immunology Dendritic Cells / metabolism Animals Receptors, CCR7 / metabolism Receptors, CCR7 / immunology Mice Humans Tumor Microenvironment / immunology T-Lymphocytes, Regulatory / immunology Neoplasms / immunology Neoplasms / pathology Chemokine CCL19 / metabolism Mice, Inbred C57BL Lymphocyte Activation / immunology CD40 Antigens / metabolism CD8-Positive T-Lymphocytes / immunology Cell Communication / immunology Dewey 610 Dewey 616.07 Dewey 616 NCI NIH HHS P01 CA240239 United States NCI NIH HHS R01 CA278212 United States Human Frontier Science Program LT000017/2021-l National Institutes of Health P01-CA240239 Deutsche Forschungsgemeinschaft 442405234 Fondation Dr Henri Dubois-FerriÃ¨re Dinu Lipatti B2201 Swiss National Science Foundation Molecular and Cellular Mechanisms Regulating Intratumoral DC3 Responses 204214 CH European Commission Deciphering tumor-promoting mechanisms mediated by neutrophils in vivo 101027235 CINPinCB EU H2020 137 Département de pathologie et immunologie 21F 4f7589ed-e44d-4850-a4d8-b0c1eccdfe48 Centre de recherche translationnelle en onco-hématologie 209 56 Département de médecine 221 false 1432 Découverte de biomarqueurs numériques pour l'oncologie de précision 1059 1293 Mécanismes de la présentation croisée des antigènes 1011 563 Pathologie et immunologie 906 1336 Comprendre et manipuler le système immunitaire pour lutter contre le cancer 1024 1388 Cancers de la femme 1040 Immunity 59 1 f1d036d1-de16-4f62-bc1f-e7e22505544e Article (Published version) Public 1-s2.0-S1074761325005229-main.pdf 9491547 application/pdf CC BY-4.0 b4aab594ac7951198117c0ce19cf1d974b834579c367024a5d13480bdf300c2e 4079b432-530f-4826-a6b3-ebc7b3672f22 Appendix Public NIHMS2134284-supplement-Supplementa.pdf 8413341 application/pdf d35aeaa6faf06fc78cd475837d4e86c4c95763d0d75c4f0bd04d9e9c11da4558 Vignette Public 1-s2.0-S1074761325005229-fx1.jpg 123798 image/png openAccess Faculté de médecine / Section de médecine fondamentale / Département de pathologie et immunologie Faculté de médecine / Centre de recherche translationnelle en onco-hématologie Faculté de médecine / Section de médecine clinique / Département de médecine

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