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Nat Commun. 2015 Jun 25;6:7458. doi: 10.1038/ncomms8458.

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

Author information

1
Department of Immunology, Roswell Park Cancer Institute, Elm &Carlton Streets, Buffalo, New York 14263, USA.
2
Center for Immunotherapy, Roswell Park Cancer Institute, Buffalo, New York 14263, USA.
3
Department of Surgical Oncology, Roswell Park Cancer Institute, Buffalo, New York 14263, USA.
4
Department of Microbiology and Immunology, University of Rochester Medical Center and the Wilmot Cancer Center, Rochester, New York 14642, USA.
5
Department of Gynecologic Oncology, Roswell Park Cancer Institute, Buffalo, New York 14263, USA.
6
Department of Medicine, University of Chicago, Chicago, Illinois 60637, USA.
7
Department of Pathology, University of Chicago, Chicago, Illinois 60637, USA.
8
Comprehensive Cancer Center and Committee on Immunology, University of Chicago, Chicago, Illinois 60637, USA.
9
Division of Rheumatology, Allergy and Immunology, Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA.

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.

PMID:
26109379
PMCID:
PMC4605273
DOI:
10.1038/ncomms8458
[Indexed for MEDLINE]
Free PMC Article

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