Steele et al. demonstrated that lymphatic vasculature helps to tune the diversity and functional state of the intratumoral CD8+ T cell repertoire and promotes tumor immune evasion. Lymphatic vessel-derived CXCL12 sequestered CD8+ T cells at the tumor periphery and facilitated CXCR4-dependent egress of a broad repertoire of functional CD8+ T cells. High-affinity antigen encounter downregulated CXCR4 and promoted T cell retention. CXCR4 inhibition, CXCR4 deletion in CD8+ T cells, or loss of lymphatic-specific CXCL12 improved T cell retention and enhanced tumor control and ICB efficacy in a preclinical melanoma model.
Contributed by Shishir Pant
ABSTRACT: 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.