1. Non-redundant requirement for CXCR3 signalling during tumoricidal T-cell trafficking across tumour vascular checkpoints.
- Author
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Mikucki ME, Fisher DT, Matsuzaki J, Skitzki JJ, Gaulin NB, Muhitch JB, Ku AW, Frelinger JG, Odunsi K, Gajewski TF, Luster AD, and Evans SS
- Subjects
- Adoptive Transfer, Animals, CD8-Positive T-Lymphocytes physiology, Cell Movement, Female, Gene Expression Regulation, Melanoma metabolism, Melanoma, Experimental genetics, Melanoma, Experimental metabolism, Mice, Mice, Knockout, Mice, Transgenic, Ovalbumin genetics, Ovalbumin metabolism, Receptors, CCR2 genetics, Receptors, CCR2 metabolism, Receptors, CCR5 genetics, Receptors, CCR5 metabolism, Receptors, CXCR3 genetics, Neoplasms blood supply, Receptors, CXCR3 metabolism, Signal Transduction physiology
- Abstract
T-cell trafficking at vascular sites has emerged as a key step in antitumour immunity. Chemokines are credited with guiding the multistep recruitment of CD8(+) T cells across tumour vessels. However, the multiplicity of chemokines within tumours has obscured the contributions of individual chemokine receptor/chemokine pairs to this process. Moreover, recent studies have challenged whether T cells require chemokine receptor signalling at effector sites. Here we investigate the hierarchy of chemokine receptor requirements during T-cell trafficking to murine and human melanoma. These studies reveal a non-redundant role for Gαi-coupled CXCR3 in stabilizing intravascular adhesion and extravasation of adoptively transferred CD8(+) effectors that is indispensable for therapeutic efficacy. In contrast, functional CCR2 and CCR5 on CD8(+) effectors fail to support trafficking despite the presence of intratumoral cognate chemokines. Taken together, these studies identify CXCR3-mediated trafficking at the tumour vascular interface as a critical checkpoint to effective T-cell-based cancer immunotherapy.
- Published
- 2015
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