Cited by 432Cancer Immunotherapy and BiomarkersT-cell and B-cell ImmunologyImmunotherapy and Immune Responses

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PD-1 Blockade Enhances T-cell Migration to Tumors by Elevating IFN-γ Inducible Chemokines

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Peng, Weiyi, Liu, Chengwen, Xu, Chunyu, Lou, Yanyan, Chen, Jieqing, Yang, Yan, Yagita, Hideo, Overwijk, Willem W., Lizée, Gregory, Radvanyi, Laszlo, Hwu, Patrick·2012·Cancer Research

DOI 10.1158/0008-5472.can-12-1187PMC PMC3476734

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Abstract

Adoptive cell transfer (ACT) is considered a promising modality for cancer treatment, but despite ongoing improvements, many patients do not experience clinical benefits. The tumor microenvironment is an important limiting factor in immunotherapy that has not been addressed fully in ACT treatments. In this study, we report that upregualtion of the immunosuppressive receptor programmed cell death-1 (PD-1) expressed on transferred T cells at the tumor site, in a murine model of ACT, compared with its expression on transferred T cells present in the peripheral blood and spleen. As PD-1 can attenuate T-cell-mediated antitumor responses, we tested whether its blockade with an anti-PD-1 antibody could enhance the antitumor activity of ACT in this model. Cotreatment with both agents increased the number of transferred T cells at the tumor site and also enhanced tumor regressions, compared with treatments with either agent alone. While anti-PD-1 did not reduce the number of immunosuppressive regulatory T cells and myeloid-derived suppressor cells present in tumor-bearing mice, we found that it increased expression of IFN-γ and CXCL10 at the tumor site. Bone marrow-transplant experiments using IFN-γR-/- mice implicated IFN-γ as a crucial nexus for controlling PD-1-mediated tumor infiltration by T cells. Taken together, our results imply that blocking the PD-1 pathway can increase IFN-γ at the tumor site, thereby increasing chemokine-dependent trafficking of immune cells into malignant disease sites.

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Authors: Peng, W., Liu, C., Xu, C., Lou, Y., Chen, J., Yang, Y., Yagita, H., Overwijk, W. W., Lizée, G., Radvanyi, L., & Hwu, P.
Affiliations: The University of Texas MD Anderson Cancer Center (US)
Authors' Affiliations: 1Department of Melanoma Medical Oncology, The Center for Cancer Immunology Research, The University of Texas MD Anderson Cancer Center, Houston, Texas; and 2Department of Immunology, Juntendo University School of Medicine, Tokyo, Japan
Corresponding author: Hwu, Patrick
ORCID: Peng, Weiyi
Liu, Chengwen
Xu, Chunyu
Lou, Yanyan
Chen, Jieqing
Yang, Yan
Radvanyi, Laszlo
Hwu, Patrick
Venue: Cancer Research
Publisher: American Association for Cancer Research (AACR)
Published: 2012-10-14
Volume: 72
Issue: 20
Pages: 5209-5218
ISSN: 0008-5472 (ISSN-L)
1538-7445
DOI: 10.1158/0008-5472.can-12-1187
PMC: PMC3476734
OpenAlex: W2116158418
Cited by: 432
References: 41
Citations by year: 2026: 18 · 2025: 25 · 2024: 27 · 2023: 38 · 2022: 47 · 2021: 31 · 2020: 30 · 2019: 40 · 2018: 38 · 2017: 34 · 2016: 33 · 2015: 34 · 2014: 17 · 2013: 18 · 2012: 2
FWCI: 11.23
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Locations: Cancer Research (publishedVersion)
PubMed (publishedVersion)
Europe PMC (PubMed Central) (acceptedVersion)
PubMed Central (acceptedVersion)
Funders: Japan Society for the Promotion of Science (22240089)
National Cancer Institute (R01CA143077, CA 016672, R01CA123182, P01CA128913, R01CA116206, P30CA016672)
National Center for Research Resources (UL1RR024148)
Topics: Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
Keywords: anti-PD-1 therapy, adoptive cell transfer, interferon-gamma, CXCL10, chemokines, tumor microenvironment, regulatory T cells, myeloid-derived suppressor cells, IFN-gamma receptor, antitumor immunity, immune cell trafficking
MeSH terms: Animals, Cell Movement, Interferon-gamma, Mice, Transgenic, Neoplasms, Experimental, T-Lymphocytes, Up-Regulation, Lymphocytes, Tumor-Infiltrating, Chemokines, Adoptive Transfer, Cell Proliferation, Mice, Programmed Cell Death 1 Receptor

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PD-1 Blockade Enhances T-cell Migration to Tumors by Elevating IFN-γ Inducible Chemokines

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