title: Non-redundant requirement for CXCR3 signalling during tumoricidal T-cell trafficking across tumour vascular checkpoints.
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.
authors.affiliation: Department of Immunology, Roswell Park Cancer Institute, Elm &Carlton Streets, Buffalo, New York 14263, USA.
authors.forename: M E
authors.initials: ME
authors.lastname: Mikucki
authors.affiliation: Department of Immunology, Roswell Park Cancer Institute, Elm &Carlton Streets, Buffalo, New York 14263, USA.
authors.forename: D T
authors.initials: DT
authors.lastname: Fisher
authors.affiliation: Center for Immunotherapy, Roswell Park Cancer Institute, Buffalo, New York 14263, USA.
authors.forename: J
authors.initials: J
authors.lastname: Matsuzaki
authors.affiliation: Department of Immunology, Roswell Park Cancer Institute, Elm &Carlton Streets, Buffalo, New York 14263, USA.|Department of Surgical Oncology, Roswell Park Cancer Institute, Buffalo, New York 14263, USA.
authors.forename: J J
authors.initials: JJ
authors.lastname: Skitzki
authors.affiliation: Department of Immunology, Roswell Park Cancer Institute, Elm &Carlton Streets, Buffalo, New York 14263, USA.
authors.forename: N B
authors.initials: NB
authors.lastname: Gaulin
authors.affiliation: Department of Immunology, Roswell Park Cancer Institute, Elm &Carlton Streets, Buffalo, New York 14263, USA.
authors.forename: J B
authors.initials: JB
authors.lastname: Muhitch
authors.affiliation: Department of Immunology, Roswell Park Cancer Institute, Elm &Carlton Streets, Buffalo, New York 14263, USA.
authors.forename: A W
authors.initials: AW
authors.lastname: Ku
authors.affiliation: Department of Microbiology and Immunology, University of Rochester Medical Center and the Wilmot Cancer Center, Rochester, New York 14642, USA.
authors.forename: J G
authors.initials: JG
authors.lastname: Frelinger
authors.affiliation: Center for Immunotherapy, Roswell Park Cancer Institute, Buffalo, New York 14263, USA.|Department of Gynecologic Oncology, Roswell Park Cancer Institute, Buffalo, New York 14263, USA.
authors.forename: K
authors.initials: K
authors.lastname: Odunsi
authors.affiliation: Department of Medicine, University of Chicago, Chicago, Illinois 60637, USA.|Department of Pathology, University of Chicago, Chicago, Illinois 60637, USA.|Comprehensive Cancer Center and Committee on Immunology, University of Chicago, Chicago, Illinois 60637, USA.
authors.forename: T F
authors.initials: TF
authors.lastname: Gajewski
authors.affiliation: Division of Rheumatology, Allergy and Immunology, Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA.
authors.forename: A D
authors.initials: AD
authors.lastname: Luster
authors.affiliation: Department of Immunology, Roswell Park Cancer Institute, Elm &Carlton Streets, Buffalo, New York 14263, USA.
authors.forename: S S
authors.initials: SS
authors.lastname: Evans
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000502:physiology; D002465:Cell Movement; D005260:Female; D005786:Gene Expression Regulation; D008545:Melanoma / Q000378:metabolism; D008546:Melanoma, Experimental / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009369:Neoplasms / Q000098:blood supply*; D010047:Ovalbumin / Q000235:genetics / Q000378:metabolism; D054390:Receptors, CCR2 / Q000235:genetics / Q000378:metabolism; D019713:Receptors, CCR5 / Q000235:genetics / Q000378:metabolism; D054367:Receptors, CXCR3 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*
chemical_list: C000592874:CCR5 protein, mouse; C515335:Ccr2 protein, mouse; C515188:Cxcr3 protein, mouse; D054390:Receptors, CCR2; D019713:Receptors, CCR5; D054367:Receptors, CXCR3; D010047:Ovalbumin