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Immunity. 2019 Jun 18;50(6):1498-1512.e5. doi: 10.1016/j.immuni.2019.04.010. Epub 2019 May 13.

Intratumoral Activity of the CXCR3 Chemokine System Is Required for the Efficacy of Anti-PD-1 Therapy.

Author information

1
Center for Immunology & Inflammatory Diseases, Division of Rheumatology, Allergy & Immunology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
2
Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
3
Cutaneous Biology Research Center, Department of Dermatology and MGH Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
4
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
5
Center for Immunology & Inflammatory Diseases, Division of Rheumatology, Allergy & Immunology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA. Electronic address: aluster@mgh.harvard.edu.

Abstract

Despite compelling rates of durable clinical responses to programmed cell death-1 (PD-1) blockade, advances are needed to extend these benefits to resistant tumors. We found that tumor-bearing mice deficient in the chemokine receptor CXCR3 responded poorly to anti-PD-1 treatment. CXCR3 and its ligand CXCL9 were critical for a productive CD8+ T cell response in tumor-bearing mice treated with anti-PD-1 but were not required for the infiltration of CD8+ T cells into tumors. The anti-PD-1-induced anti-tumor response was facilitated by CXCL9 production from intratumoral CD103+ dendritic cells, suggesting that CXCR3 facilitates dendritic cell-T cell interactions within the tumor microenvironment. CXCR3 ligands in murine tumors and in plasma of melanoma patients were an indicator of clinical response to anti-PD-1, and their induction in non-responsive murine tumors promoted responsiveness to anti-PD-1. Our data suggest that the CXCR3 chemokine system is a biomarker for sensitivity to PD-1 blockade and that augmenting the intratumoral function of this chemokine system could improve clinical outcomes.

KEYWORDS:

CD8(+) T cells; CXCL10; CXCL9; CXCR3; PD-1; chemokine; dendritic cells; immune checkpoint; immunotherapy

Comment in

PMID:
31097342
PMCID:
PMC6527362
[Available on 2020-06-18]
DOI:
10.1016/j.immuni.2019.04.010
[Indexed for MEDLINE]

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