Résumé
Trafficking of tumor-reactive T cells across vascular checkpoints is a critical juncture in the effector phase of cancer immunity although this step is largely unexplored. We recently showed that poor trafficking of blood-borne CD8 effector T cells across tumor microvascular checkpoints is a significant obstacle to antitumor immunity. This bottleneck can be overcome by preconditioning regimens using systemic thermal therapy (STT, 39.5 ± 0.5°C, 6 h) that promotes E/P-selectin and ICAM-1-dependent trafficking of adoptively transferred CD8 T cells and subsequent lysis of tumor targets. Here we investigated the chemokine receptor requirements for trafficking of tumor-specific OT-I CD8 T cells across microvascular barriers in B16-OVA murine melanoma. We identified a non-redundant role for CXCR3, but not CXCR4, in T cell trafficking to tumors under both homeostatic and STT conditions using CXCR3-deficient OT-I T cells. Parallel results were observed by intravital microscopy whereby CXCR3 was necessary for T cells to undergo chemokine-dependent transition from rolling to firm arrest in tumor vessels of STT-pretreated mice. Taken together, these studies provide the first evidence that CXCR3 is obligatory for T cell trafficking across tumor vascular gateways and support strategic use of therapies to augment chemokine-dependent delivery of immune cells for the treatment of cancer. Supported by the NIH (CA79765, CA085183), and the Jennifer Linscott Tietgen Family Foundation.