T cell Egress via Lymphatic Vessels Limits the Intratumoral T cell Repertoire in Melanoma

Abstract

Antigen-specific CD8+ T cell accumulation in tumors is a prerequisite for effective immunotherapy, and yet, the mechanisms of lymphocyte transit remain poorly defined. We find that tumor-associated lymphatic vessels control T cell exit from tumors via the chemokine CXCL12, and intratumoral antigen encounter tunes CXCR4 expression on 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 exit the tumor, thereby limiting tumor control. CXCR4 inhibition and loss of lymphatic-specific CXCL12 boosts T cell retention and enhances response to therapeutic immune checkpoint blockade. Strategies that limit T cell egress, therefore, provide a new tool to boost immunotherapy response.

Three-dimensional imaging and single-cell transcriptomics of the human kidney implicate perturbation of lymphatics in alloimmunity

“…Lymphatics display a distinct molecular profile from their blood vascular counterparts in chronic rejection, expressing immune inhibitory molecules with the potential to regulate local alloreactive CD4 + T cells. These findings, akin to those recently delineated for mouse tumour (Gkountidi et al 2021;Steele et al 2022), central nervous system (Hsu et al 2022) and dermal lymphatics (Churchill et al 2022), suggest lymphatics modulate adaptive immune responses within the tissue microenvironment, beyond their roles in leukocyte egress; implicating these vessels as an emerging therapeutic target in chronic transplant rejection (Gupta et al 2012;Sun et al 2021).…”

CXCR6 promotes dermal CD8+T cell survival and transition to long-term tissue residence

“…As previously reported, T RM CD8 + T cells exhibited lower expression of S1pr1 relative to T CIRC , consistent with its proposed role in tissue egress ( 3 ). Of note, little Ccr7 expression was seen in any subset, instead T CIRC cells expressed elevated levels of Cxcr4 , which facilitates egress from melanoma through CXCL12-producing dermal lymphatic vessels ( 24 ). In addition to several receptors including, S1pr4, Ccr2, Ccr5 , and Cxcr3, Cxcr6 was significantly enriched in T RM relative to T CIRC ( Fig 1I and S1F) , indicating that the high surface expression observed across T RM transcriptional states likely depended upon a transcriptional event that occurred after tissue entry.…”

“…and depends on local antigen recognition. We recently demonstrated in tumors that local antigen encounter downregulates CXCR4, which acts as a mechanism of tumor egress ( 24 ), and in concordance Cxcr4 was transcriptionally downregulated in cells transitioning to residence following infection. In contrast, and as expected based on data presented here, CXCR6 was enriched on tumor-retained CD8 + T cells that exhibited signs of chronic antigen stimulation ( 24 ).…”

“…We recently demonstrated in tumors that local antigen encounter downregulates CXCR4, which acts as a mechanism of tumor egress ( 24 ), and in concordance Cxcr4 was transcriptionally downregulated in cells transitioning to residence following infection. In contrast, and as expected based on data presented here, CXCR6 was enriched on tumor-retained CD8 + T cells that exhibited signs of chronic antigen stimulation ( 24 ). Interestingly, tissue entry and initial antigen presentation may be tightly linked in infected skin presenting the possibility that Cxcr6 upregulation occurs rapidly in a dermal, perivascular niche ( 48 ), where at least in tumors, the CXCL16-expressing dendritic cells reside ( 10 ).…”