Beatrice Zitti, Florent Duval, Pratyaksha Wirapati, Mehdi Hicham, Yuxuan Xie, Juhyun Oh, Jan Hoelzl, Philippa Meiser, Marco Varrone, Hannah M. Peterson, Chiara Cianciaruso, Ruben Bill, Felix Bayerl, Evangelia Bolli, Anne-Gaëlle Goubet, Máté Kiss, Sheri McDowell, Phil Cheng, Dan Celestini, Julie Terzic, Thomas Zwahlen, Nagham Alouche, Nawel Zouggari, David Tarussio, Stephanie Tissot, Paula Nunes-Hasler, Mari Mino-Kenudson, Michael Lanuti, William C. Faquin, Peter M. Sadow, Jean-Christophe Tille, Sana Intidhar Labidi-Galy, Christopher S. Garris, Stephanie Hugues, Tatiana V. Petrova, Burkhard Ludewig, Sergio Quezada, Sanjiv Luther, Thorsten R. Mempel, Giovanni Ciriello, Sara I. Pai, Olivier Michielin, Jan P. Böttcher, Ralph Weissleder, Mikael J. Pittet
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.