Non-redundant Requirement for CXCR3 Chemokine Receptor Signaling in Trafficking of Tumoricidal T cells across Tumor Vascular Barriers

Cancer immunotherapy aims to generate long-lived, tumor-specific adaptive immunity to limit dysregulated tumor progression and metastasis. Therapeutic success has been particularly challenging to achieve because of the local, cytokine-rich inflammatory milieu that drives a pro-tumorigenic program supporting the growth and survival of malignant cells. T cell trafficking at tumor vascular loci has emerged as a critical step in successful antitumor immunity and cancer immunotherapy since it is the main access point for cytotoxic T cells to reach tumor cell targets. The prevailing view is that chemokines provide essential guidance cues for this process, however there is surprisingly little known about the molecular mechanisms governing T cell trafficking at the tumor vascular interface. In this regard, the multiplicity of chemokines found in cancer lesions has obscured contributions of individual chemokine receptor/chemokine pairs to the multistep recruitment of CD8+ T cells across tumor vessels. Moreover, recent studies have challenged whether prototypical G &agr;i-coupled chemokine receptor signaling is even required for T cell trafficking at effector sites.;Here, we investigated the hierarchy of chemokine receptor requirements during trafficking of blood-borne effector T cells to murine B16 melanoma as well as human melanoma xenografts. These studies unexpectedly revealed a non-redundant role for G&agr;i-coupled CXCR3 in stabilizing intravascular adhesion and subsequent extravasation of murine CD8+ effector T cells that was indispensable for the therapeutic efficacy of adoptively transferred T cells. In contrast, functional CC chemokine receptor 2 (CCR2) and CCR5 on CD8+ effectors failed to support trafficking despite the presence of intravascular cognate chemokines. The obligate role for CXCR3 was further maintained during human effector T cell homing in melanoma xenografts. Taken together, these studies identify CXC chemokine Receptor 3 (CXCR3)-mediated trafficking at the tumor vascular interface as a critical checkpoint to effective T cell-based cancer immunotherapy. Furthermore, information regarding the requirement for the CXCR3/CXCR3 ligand axis during T cell homing suggests that there may be a therapeutic benefit to employing chemokine-based treatments as an adjuvant to T cell-based immunotherapy in cancer patients.