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PD-1 Blockade Enhances T-cell Migration to Tumors by Elevating IFN-γ Inducible Chemokines
Open accessPublished version of a preprint
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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“Indeed, mouse models have shown that local IFN-γ upregulation is essential for anti-PD-1-mediated tumor regression (89).”
From Anti-PD-1 and Anti-CTLA-4 Therapies in Cancer: Mechanisms of Action, Efficacy, and Limitations (2018) · cites this paper as [89]
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Metadata
- 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
- Venue
- Cancer Research
- Published
- 2012-10-14
- Volume
- 72
- Issue
- 20
- Pages
- 5209-5218
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- 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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