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

Author

Listed:
  • 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.
    Roswell Park Cancer Institute)

  • 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
    Roswell Park Cancer Institute)

  • T. F. Gajewski

    (University of Chicago
    University of Chicago
    Comprehensive Cancer Center and Committee on Immunology, 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.)

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.

Suggested Citation

  • 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 & S. S. Evans, 2015. "Non-redundant requirement for CXCR3 signalling during tumoricidal T-cell trafficking across tumour vascular checkpoints," Nature Communications, Nature, vol. 6(1), pages 1-14, November.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms8458
    DOI: 10.1038/ncomms8458
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    1. Siqi Li & Kun Li & Kang Wang & Haoyuan Yu & Xiangyang Wang & Mengchen Shi & Zhixing Liang & Zhou Yang & Yongwei Hu & Yang Li & Wei Liu & Hua Li & Shuqun Cheng & Linsen Ye & Yang Yang, 2023. "Low-dose radiotherapy combined with dual PD-L1 and VEGFA blockade elicits antitumor response in hepatocellular carcinoma mediated by activated intratumoral CD8+ exhausted-like T cells," Nature Communications, Nature, vol. 14(1), pages 1-21, December.

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