Advancing Education, Research, and Quality of Care for the Head and Neck oncology patient.
Head and neck squamous cell carcinoma exerts broad suppressive effects on the immune macroenvironment, disrupting dendritic cell (DC) function and undermining antitumor surveillance. We previously characterized the essential role of conventional dendritic cells (cDCs) within tumor-draining lymph nodes in mediating the response to immune checkpoint inhibition therapy, demonstrating that an intact and functional lymphatic-immune interface is critical for effective antitumor immunity. Additionally, we have recently described the influence of G protein- coupled receptor signaling on the activity of key antitumor CD8 T cells in the tumor micorenvironment. Building on these findings, we hypothesize that intratumoral chemokine priming with G protein-coupled receptor ligands CXCL10 and XCL1 drives both the recruitment and activation of key cDC and CD8 T cell effectors to overcome tumor-driven immunosuppression, potentiating immune checkpoint inhibition and the host response to therapy.
Using syngeneic models of HNSCC, we investigated the capacity of CXCL10, which targets CXCR3-expressing T and natural killer cells, and XCL1, which engages XCR1-expressing cDC1s, to both recruit and activate immune effectors across the tumor-lymphatic axis. To explore the ability of chemokine priming to reprogram the tumor immune landscape, we assessed changes in immune cell distribution, trafficking, and functionality within the tumor microenvironment and tumor-draining lymph nodes using single-cell and spatial profiling technologies, including CyTOF, quantitative immunofluorescence, and single-cell RNA sequencing. Our results indicate that chemokine priming activated both cDC1s and CD8 T cells, polarizing both populations towards antitumor effector phenotypes. Local delivery of CXCL10 and XCL1 significantly enhanced infiltration and activation of cytotoxic CD8 T cells, natural killer cells, and functional cDC1s within the tumor microenvironment, restoring immune surveillance and improving responses to immune checkpoint inhibition. Notably, CXCL10 treatment promoted durable CD8 T cell presence and tumor regression with immune memory, while XCL1 facilitated cDC1 migration to tumor-draining lymph nodes, promoting effective CD8 T cell priming and amplifying antitumor cytotoxicity. Finally, combined CXCL10/XCL1 priming with PD-1 blockade resulted in complete and durable tumor response.
Overall, our findings underscore the therapeutic potential of local chemokine priming as a strategy to reset the immune macroenvironment through recruitment and activation of key antitumor cDC and CD8 T cell populations that potentiate the host response to immune checkpoint inhibition.