[HTML][HTML] Non-redundant requirement for CXCR3 signalling during tumoricidal T-cell trafficking across tumour vascular checkpoints

ME Mikucki, DT Fisher, J Matsuzaki, JJ Skitzki… - Nature …, 2015 - nature.com
ME Mikucki, DT Fisher, J Matsuzaki, JJ Skitzki, NB Gaulin, JB Muhitch, AW Ku, JG Frelinger…
Nature communications, 2015nature.com
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 …
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.
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