Abstract

--- - Here, the authors show that CD8(+) T cells egress from tumors via lymphatic vessels in a CXCL12/CXCR4-dependent manner. High-affinity antigen encounter inhibits CXCR4 and increases retention, while no encounter or weak affinity directs T cell exit to limit local tumor control. - Antigen-specific CD8(+) T cell accumulation in tumors is a prerequisite for effective immunotherapy, and yet the mechanisms of lymphocyte transit are not well defined. Here we show that tumor-associated lymphatic vessels control T cell exit from tumors via the chemokine CXCL12, and intratumoral antigen encounter tunes CXCR4 expression by effector CD8(+) T cells. Only high-affinity antigen downregulates CXCR4 and upregulates the CXCL12 decoy receptor, ACKR3, thereby reducing CXCL12 sensitivity and promoting T cell retention. A diverse repertoire of functional tumor-specific CD8(+) T cells, therefore, exit the tumor, which limits the pool of CD8(+) T cells available to exert tumor control. CXCR4 inhibition or loss of lymphatic-specific CXCL12 boosts T cell retention and enhances tumor control. These data indicate that strategies to limit T cell egress might be an approach to boost the quantity and quality of intratumoral T cells and thereby response to immunotherapy.