The CD83 axis between Tregs and CCR7+ dendritic cells governs anti-tumor immune responses 2309951

Abstract

Immune checkpoint blockade (ICB) has advanced the treatment of melanoma and other cancer types. Despite its success, only about half of the treated patients respond, with many developing resistances. One contributing factor is the poor infiltration of effector T cells in the solid tumors, along with the immunosuppression caused by regulatory T (Treg) cells. CCR7+ dendritic cells (DC) interact with T cells, by either supporting the survival of CD8 T cells or promoting the migration of Tregs. While they are known to play a role in mediating tumor immune responses, their specific functions in controlling tumors and T cell responses remain poorly understood. We generated innovative mouse models such as the inducible CCR7+DC conditional knock out (cKO), to defined how CCR7+DC use CD83 to restrain CD8 T cell effector responses and promote tumor growth. Reducing the expression of the activation maker CD83 on CCR7+DC, either directly or via blocking its soluble form expressed by Tregs, enhanced intratumoral CD8 T cell accumulation and controlled tumor growth in mice. Genetic perturbation of CD83 retains a pro-inflammatory IL-12+ CCR7+DC state, which is associated with the expansion of effector-like CD8 T cells and improved tumor control. Mechanistically, Tregs regulate IL-12 expression on CCR7+DC via STAT signaling in a CD83 dependent manner in vitro. Furthermore, we also show that CD83 levels on CCR7+DC negatively correlate with intratumoral CD8 T cell infiltration in several human cancers. This study demonstrates that the ablation of interaction of CD83 molecule between CCR7+DC and Tregs results in increased anti-tumor immune response. Our findings identify CD83 as a cellular and molecular checkpoint that restrains T cell responses and can be targeted therapeutically. This work was supported by funding for M.D.P from Cancer Prevention and Research Institute of Texas (CPRIT; RR210017) Robert J. Kleberg, Jr. and Helen C. Foundation Melanoma SPORE Developmental Research Program (DRP; P50CA221703) American Association of I Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)