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

M E Mikucki,D T Fisher,J G Frelinger,T F Gajewski,A W Ku,J J Skitzki,J B Muhitch,N B Gaulin,K Odunsi,S S Evans,J Matsuzaki,A D Luster

doi:10.1038/ncomms8458

M E Mikucki, D T Fisher + Show 10 more

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https://doi.org/10.1038/ncomms8458

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T cell trafficking at vascular sites has emerged as a key step in antitumor immunity. Chemokines are credited with guiding the multistep recruitment of CD8+ T cells across tumor vessels. However, the multiplicity of chemokines within tumors has obscured the contributions of individual chemokine receptor/chemokine pairs to this process. Moreover, recent studies have challenged whether T cells require chemokine receptor signaling 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 tumor vascular interface as a critical checkpoint to effective T cell-based cancer immunotherapy.

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T-cell trafficking at vascular sites has emerged as a key step in antitumour immunity
High concentrations (B1 ng per mg total protein) of CXCL9, CXCL10, CCL5 (CCR5 ligand) and CCL2 (CCR2 ligand) were detected in B16-OVA tumour extracts compared with non-inflamed normal skin following subcutaneous (s.c.) injection of phosphate buffered saline (PBS) (Fig. 1a)
WT OT-I effector populations (496% CD8 þ CD44hi, Supplementary Fig. 1a) exhibited strong migration to recombinant CXCL9, CXCL10, CCL5 and CCL2, which was blocked by pertussis toxin (PTX), a global inhibitor of Gai protein-coupled chemokine receptor signalling (Fig. 1b)

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T-cell trafficking at vascular sites has emerged as a key step in antitumour immunity. 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 Gai-coupled CXCR3 in stabilizing intravascular adhesion and extravasation of adoptively transferred CD8 þ effectors that is indispensable for therapeutic efficacy. Insight into the role of chemokines in the tumour microenvironment stems from correlative studies linking T-cell accumulation with multiple chemokine receptors on effector T cells and/or chemokines within the tumour locale[1,20,21] In this regard, expression of CXCR3 on circulating T cells or its chemokine ligands, CXCL9 and CXCL10, in tumour tissues is associated with elevated intratumoral T-cell infiltration and a favourable outcome in melanoma and colorectal cancer patients[1,20,21,22]. These findings identify CXCR3 interactions with cognate chemokines within the vessel wall as a critical checkpoint dictating the efficacy of T-cell-based cancer immunotherapy

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