Résumé
Recent advances in the treatment of metastatic melanoma are designed to promote the cytotoxic CD8 T cell response (e.g., CTLA-4 blockade and adoptive cell transfer), but it remains poorly understood how T cells enter tumor tissues to contact tumor targets. Here, we investigated the hierarchy of chemokine receptor requirements during the trafficking of blood-borne T cells to melanoma tumors by studying three molecules associated with infiltration, i.e., CCR2, CCR5, and CXCR3. These studies used B16-F10 murine melanoma to discriminate the contributions of individual chemokine receptors to T cell trafficking as opposed to T cell retention, proliferation, and survival in situ. Tumor-reactive cytotoxic T cells expressed functional CCR2, CCR5, and CXCR3 in vitro, and their cognate chemokines (CCL2, CCL5, and CXCL10, respectively) were also detected in the tumor microenvironment. Unexpectedly, loss of CCR2 and CCR5 did not impact T cell delivery to melanoma tissues; only CXCR3 was required for extravasation of adoptively transferred T cells in tumors. Intravital microscopy further revealed that T cells require CXCR3 to transition from transient rolling to firm arrest during the stepwise migration cascade at the tumor vascular interface. Taken together, these studies establish the obligate role for CXCR3 in the migration of effector T cells into tumor tissue and support the development of chemokine-targeted strategies to improve T cell entry during cancer immunotherapy.