Cited by 723Cancer Immunotherapy and BiomarkersChemokine receptors and signalingT-cell and B-cell Immunology

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

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Chow, Melvyn T., Ozga, Aleksandra J., Servis, Rachel L., Frederick, Dennie T., Lo, Jennifer A., Fisher, David E., Freeman, Gordon J., Boland, Genevieve M., Luster, Andrew D.·2019·Immunity

DOI 10.1016/j.immuni.2019.04.010PMC PMC6527362

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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.

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Authors: Chow, M. T., Ozga, A. J., Servis, R. L., Frederick, D. T., Lo, J. A., Fisher, D. E., Freeman, G. J., Boland, G. M., & Luster, A. D.
Affiliations: Harvard University (US)
Corresponding author: Luster, Andrew D.
ORCID: Ozga, Aleksandra J.
Frederick, Dennie T.
Lo, Jennifer A.
Fisher, David E.
Freeman, Gordon J.
Boland, Genevieve M.
Luster, Andrew D.
Venue: Immunity
Publisher: Elsevier BV
Published: 2019-06
Volume: 50
Issue: 6
Pages: 1498-1512.e5
ISSN: 1074-7613 (ISSN-L)
DOI: 10.1016/j.immuni.2019.04.010
PMC: PMC6527362
OpenAlex: W2945224722
Cited by: 716
References: 57
Citations by year: 2026: 83 · 2025: 98 · 2024: 120 · 2023: 128 · 2022: 96 · 2021: 90 · 2020: 81 · 2019: 19
FWCI: 30.30
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
www.elsevier.com/open-access/userlicense/1.0/ (vor, 384 d)
Locations: Immunity (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
Funders: Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (AR043369)
Dr. Miriam and Sheldon G. Adelson Medical Research Foundation
National Institutes of Health (AR043369, CA204028, AI112521, CA222871, CA163222)
Melanoma Research Alliance
Cancer Research Institute
Topics: Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
Health Sciences › Medicine › Oncology › Chemokine receptors and signaling
Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
Keywords: CXCR3, CXCL9, anti-PD-1 therapy, chemokine system, CD8+ T cells, CD103+ dendritic cells, dendritic cell-T cell interaction, tumor microenvironment, melanoma, predictive biomarkers, immunotherapy resistance
MeSH terms: Antineoplastic Agents, Immunological, Animals, Disease Models, Animal, Humans, Lymphocyte Activation, Neoplasms, Biomarkers, T-Lymphocyte Subsets, Mice, Knockout, CD8-Positive T-Lymphocytes, Xenograft Model Antitumor Assays, Epigenesis, Genetic, Mice, Receptors, CXCR3, Immunomodulation, Molecular Targeted Therapy, Tumor Microenvironment, Programmed Cell Death 1 Receptor

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

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