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.
Zitti et al. (Mon,) studied this question.