Zitti Beatrice, Duval Florent, Wirapati Pratyaksha, Hicham Mehdi, Xie Yuxuan, Oh Juhyun, Hoelzl Jan, Meiser Philippa, Varrone Marco, Peterson Hannah M, Cianciaruso Chiara, Bill Ruben, Bayerl Felix, Bolli Evangelia, Goubet Anne-Gaëlle, Kiss Máté, McDowell Sheri, Cheng Phil, Celestini Dan, Terzic Julie, Zwahlen Thomas, Alouche Nagham, Zouggari Nawel, Tarussio David, Tissot Stephanie, Nunes-Hasler Paula, Mino-Kenudson Mari, Lanuti Michael, Faquin William C, Sadow Peter M, Tille Jean-Christophe, Intidhar Labidi-Galy Sana, Garris Christopher S, Hugues Stephanie, Petrova Tatiana V, Ludewig Burkhard, Quezada Sergio, Luther Sanjiv, Mempel Thorsten R, Ciriello Giovanni, Pai Sara I, Michielin Olivier, Böttcher Jan P, Weissleder Ralph, Pittet Mikael J
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.
Center for Systems Biology, Massachusetts General Brigham and Harvard Medical School, Boston, MA, USA.
Immunity. 2026 Jan 13;59(1):161-176.e12. doi: 10.1016/j.immuni.2025.11.020. Epub 2025 Dec 19.
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.
肿瘤驻留的CCR7树突状细胞（DCs）是抗肿瘤T细胞反应的关键决定因素。在此，我们研究了CCR7 DCs在肿瘤内的定位及其定位对抗肿瘤免疫的影响。对人类癌症和小鼠模型的空间、单细胞及活体分析表明，CCR7 DCs形成血管周围簇。静脉血管周围的成纤维细胞产生CCL19，引导CCR7 DCs进入血管周围微环境。调节性T（Treg）细胞经常与血管周围的CCR7 DCs接触，抑制CD40表达以及CD4和CD8 T细胞活化。去除Treg细胞可恢复CCR7 DCs的CD40表达，增强免疫刺激程序，并改善T细胞依赖性肿瘤控制。抗PD-1不仅增加血管周围CCR7 DCs的聚集和IL-12产生，还通过CCL22依赖性机制加强Treg-DC相互作用，限制治疗效果。CCR7 DCs表达共刺激分子和共抑制分子，这可能是其具有抗肿瘤激活能力及同时易受抑制的基础。调节形成和限制CCR7 DC血管周围免疫枢纽的机制可能会改善癌症免疫治疗。
