PD-L1/B7H-1 Inhibits the Effector Phase of Tumor Rejection by T Cell Receptor (TCR) Transgenic CD8+ T Cells
Open accessAbstract
Although increased circulating tumor antigen-specific CD8+ T cells can be achieved by vaccination or adoptive transfer, tumor progression nonetheless often occurs through resistance to effector function. To develop a model for identifying mechanisms of resistance to antigen-specific CTLs, poorly immunogenic B16-F10 melanoma was transduced to express the Kb-binding peptide SIYRYYGL as a green fluorescent protein fusion protein that should be recognized by high-affinity 2C TCR transgenic T cells. Although B16.SIY cells expressed high levels of antigen and were induced to express Kb in response to IFN-γ, they were poorly recognized by primed 2C/RAG2−/− T cells. A screen for candidate inhibitory ligands revealed elevated PD-L1/B7H-1 on IFN-γ-treated B16-F10 cells and also on eight additional mouse tumors and seven human melanoma cell lines. Primed 2C/RAG2−/−/PD-1−/− T cells showed augmented cytokine production, proliferation, and cytolytic activity against tumor cells compared with wild-type 2C cells. This effect was reproduced with anti-PD-L1 antibody present during the effector phase but not during the priming culture. Adoptive transfer of 2C/RAG2−/−/PD-1−/− T cells in vivo caused tumor rejection under conditions in which wild-type 2C cells or CTLA-4-deficient 2C cells did not reject. Our results support interfering with PD-L1/PD-1 interactions to augment the effector function of tumor antigen-specific CD8+ T cells in the tumor microenvironment.
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In the tumor microenvironment, stimulatory and inhibitory B7 family members are imbalanced, with high inhibitory and low stimulatory expression.
“There is an active imbalance between stimulatory and inhibitory B7 family members in the tumor microenvironment [1,3,7,8].”
From T cell anergy, exhaustion, senescence, and stemness in the tumor microenvironment (2013) · cites this paper as [8]
In animal models, introducing B7-1 into tumors or blocking inhibitory B7 family members reduces tumor growth or causes spontaneous tumor rejection.
“Animal model studies have shown that introduction of B7-1 into tumors by transfection or blockade of inhibitory B7 family members can reduce tumor growth or result in spontaneous tumor rejection in vivo [7–13].”
From T cell anergy, exhaustion, senescence, and stemness in the tumor microenvironment (2013) · cites this paper as [8]
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- Authors
- Blank, C., Brown, I., Peterson, A. C., Spiotto, M., Iwai, Y., Honjo, T., & Gajewski, T. F.
- Affiliations
- 1Departments of Pathology and
- University of Chicago (US)
- Kyoto University (JP)
- Venue
- Cancer Research
- Published
- 2004-02-01
- Volume
- 64
- Issue
- 3
- Pages
- 1140-1145
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- OpenAlex
- W2111217091
- Cited by
- 772
- References
- 3
- Citations by year
- 2026: 5 · 2025: 23 · 2024: 34 · 2023: 29 · 2022: 41 · 2021: 41 · 2020: 52 · 2019: 44 · 2018: 74 · 2017: 72 · 2016: 54 · 2015: 61 · 2014: 26 · 2013: 34 · 2012: 31
- FWCI
- 10.23
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Bundesministerium für Bildung und Forschung
- National Institutes of Health
- National Cancer Institute (P01CA97296, P01CA097296)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Keywords
- PD-1, tumor rejection, CD8+ T cells, T cell receptor transgenic T cells, B16F10 melanoma, antigen-specific cytotoxic T lymphocytes, effector phase, adoptive T cell therapy, CTLA-4, interferon-gamma, tumor immunogenicity, tumor microenvironment, melanoma
- MeSH terms
- Animals, Antibodies, Monoclonal, Antigens, Differentiation, Blood Proteins, Interferon-gamma, Membrane Glycoproteins, Mice, Transgenic, Neoplasms, Experimental, Peptides, Receptors, Antigen, T-Cell, Transduction, Genetic, Antigens, CD, Up-Regulation, B7-1 Antigen, CD8-Positive T-Lymphocytes, Mice, B7-H1 Antigen, CTLA-4 Antigen
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