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

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adoptive Transfer
  • Animals
  • CD8-Positive T-Lymphocytes / physiology
  • Cell Movement
  • Female
  • Gene Expression Regulation
  • Melanoma / metabolism
  • Melanoma, Experimental / genetics
  • Melanoma, Experimental / metabolism
  • Mice
  • Mice, Knockout
  • Mice, Transgenic
  • Neoplasms / blood supply*
  • Ovalbumin / genetics
  • Ovalbumin / metabolism
  • Receptors, CCR2 / genetics
  • Receptors, CCR2 / metabolism
  • Receptors, CCR5 / genetics
  • Receptors, CCR5 / metabolism
  • Receptors, CXCR3 / genetics
  • Receptors, CXCR3 / metabolism*
  • Signal Transduction / physiology*

Substances

  • CCR5 protein, mouse
  • Ccr2 protein, mouse
  • Cxcr3 protein, mouse
  • Receptors, CCR2
  • Receptors, CCR5
  • Receptors, CXCR3
  • Ovalbumin