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

M. E. Mikucki, D. T. Fisher, J. Matsuzaki, J. J. Skitzki, N. B. Gaulin, J. B. Muhitch, A. W. Ku, J. G. Frelinger, K. Odunsi, T. F. Gajewski, A. D. Luster and S. S. Evans ()
Additional contact information
M. E. Mikucki: Roswell Park Cancer Institute, Elm & Carlton Streets, Buffalo, New York 14263, USA.
D. T. Fisher: Roswell Park Cancer Institute, Elm & Carlton Streets, Buffalo, New York 14263, USA.
J. Matsuzaki: Center for Immunotherapy, Roswell Park Cancer Institute
J. J. Skitzki: Roswell Park Cancer Institute, Elm & Carlton Streets, Buffalo, New York 14263, USA.
N. B. Gaulin: Roswell Park Cancer Institute, Elm & Carlton Streets, Buffalo, New York 14263, USA.
J. B. Muhitch: Roswell Park Cancer Institute, Elm & Carlton Streets, Buffalo, New York 14263, USA.
A. W. Ku: Roswell Park Cancer Institute, Elm & Carlton Streets, Buffalo, New York 14263, USA.
J. G. Frelinger: University of Rochester Medical Center and the Wilmot Cancer Center
K. Odunsi: Center for Immunotherapy, Roswell Park Cancer Institute
T. F. Gajewski: University of Chicago
A. D. Luster: Allergy and Immunology, Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Harvard Medical School
S. S. Evans: Roswell Park Cancer Institute, Elm & Carlton Streets, Buffalo, New York 14263, USA.

Nature Communications, 2015, vol. 6, issue 1, 1-14

Abstract: 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.

Date: 2015
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DOI: 10.1038/ncomms8458

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