A number of promising T cell-based cancer immunotherapies have recently come to the forefront in the treatment of metastatic melanoma. However, despite major advances in strategies that target the function (i.e., the anti-CTLA-4 blocking antibody, ipilimumab) or frequency (i.e., adoptive T cell transfer therapy) of circulating tumor-restricted cytotoxic T cells, complete clinical responses have been modest. A common denominator of all T cell-based therapies is the requirement for chemokine-dependent delivery of blood-borne T cells across tumor vascular barriers for cytolysis of tumor targets. Chemokines have emerged as master- regulators of effector T cell trafficking by triggering stable adhesive interactions that direct T cell migration out of vessels and into underlying tissue. We have recently identified an obligate role for a specific chemokine receptor, CXCR3, in supporting anti-tumorigenic T cell trafficking within tumor vessels. Surprisingly, CXCR3 is also expressed by many human and murine tumors where it has a pro-tumorigenic role in mediating metastatic tumor spread. Coincident expression of CXCR3 by both T cells and tumor cells raises the possibility that neoplastic cells that are the major constituents of tumor tissue may have an overlooked role in competing for finite amounts of chemokine within the local tumor microenvironment. These observations led to the central hypothesis being tested that melanoma cells expressing CXCR3 evade antitumor immunity by scavenging local chemokines required for T cell recruitment. Complimentary, but independent, studies will address potential mechanisms by which tumor cells may interfere with chemokine bioavailability by tracking the fate of fluorescently-tagged chemokine after incubation with tumor cells. Alternatively, we will take a loss of function approach to diminish CXCR3 expression on tumor cells and determine the subsequent impact on T cell trafficking in the tumor microenvironment. Finally, we will link chemokine-dependent T cell entry to tumor cell apoptosis as an early indicator of antitumor immunity. These studies are expected to reveal a novel mechanism of melanoma resistance to immunotherapy and lay the foundation for the translation of CXCR3 blockade as a preconditioning regimen in cancer patients prior to T cell-based immunotherapy.
The outlook for patients with metastatic melanoma remains dismal despite overall improvement in cancer patient survival. Recent advances have renewed interest in developing T-cell mediated immune therapies for melanoma and other cancer patients. However, limitations in trafficking of cytotoxic T cells into tumors remain a critical obstacle to antitumor immune responses. These studies explore the novel hypothesis that tumor cells interfere with T cell recruitment by sequestering essential trafficking molecules required fo entry and may suggest strategies to improve T cell-mediated therapies in patients.
|Mikucki, M E; Fisher, D T; Matsuzaki, J et al. (2015) Non-redundant requirement for CXCR3 signalling during tumoricidal T-cell trafficking across tumour vascular checkpoints. Nat Commun 6:7458|