Tumor-infiltrating NY-ESO-1–specific CD8 + T cells are negatively regulated by LAG-3 and PD-1 in human ovarian cancer
Open accessAbstract
NY-ESO-1 is a "cancer-testis" antigen frequently expressed in epithelial ovarian cancer (EOC) and is among the most immunogenic tumor antigens defined to date. In an effort to understand in vivo tolerance mechanisms, we assessed the phenotype and function of NY-ESO-1-specific CD8(+) T cells derived from peripheral blood lymphocytes (PBLs), tumor-infiltrating lymphocytes (TILs), and tumor-associated lymphocytes (TALs) of EOC patients with NY-ESO-1-expressing tumors, with or without humoral immunity to NY-ESO-1. Whereas NY-ESO-1-specific CD8(+) T cells were readily detectable ex vivo with tetramers in TILs and TALs of seropositive patients, they were only detectable in PBLs following in vitro stimulation. Compared with PBLs, tumor-derived NY-ESO-1-specific CD8(+) T cells demonstrated impaired effector function, preferential usage of dominant T-cell receptor, and enriched coexpression of inhibitory molecules LAG-3 and PD-1. Expression of LAG-3 and PD-1 on CD8(+) T cells was up-regulated by IL-10, IL-6 (cytokines found in tumor ascites), and tumor-derived antigen-presenting cells. Functionally, CD8(+)LAG-3(+)PD-1(+) T cells were more impaired in IFN-gamma/TNF-alpha production compared with LAG-3(+)PD-1(-) or LAG-3(-)PD-1(-) subsets. Dual blockade of LAG-3 and PD-1 during T-cell priming efficiently augmented proliferation and cytokine production by NY-ESO-1-specific CD8(+) T cells, indicating that antitumor function of NY-ESO-1-specific CD8(+) T cells could potentially be improved by therapeutic targeting of these inhibitory receptors.
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LAG-3 is expressed on various immune cells, inhibits CD8+ T cell function, and increases the immunosuppressive behavior of Tregs.
“it is known to have an inhibitory role on CD8+ T cell function (Matsuzaki et al., 2010) and increases the immunosuppressive behavior of Tregs (Yano et al., 2019).”
From Hallmarks of response, resistance, and toxicity to immune checkpoint blockade (2021) · cites this paper as Matsuzaki et al., 2010
LAG3 highly expressed on tumor-infiltrating lymphocytes interacts with tumor cell surface ligands to cause T cell dysfunction or exhaustion, promoting tumor immune escape, particularly in CD8+ T cells.
“LAG3, highly expressed on the tumor‐infiltrating lymphocytes (TILs), interacts with ligands located on the surface of tumor cells to cause T cell dysfunction or even exhaustion, promoting tumor immune escape, particularly evident in CD8+ T cells [329, 330].”
From Tumor microenvironment signaling and therapeutics in cancer progression (2023) · cites this paper as [330]
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- Authors
- Matsuzaki, J., Gnjatic, S., Mhawech-Fauceglia, P., Beck, A., Miller, A., Tsuji, T., Eppolito, C., Qian, F., Lele, S., Shrikant, P., Old, L. J., & Odunsi, K.
- Affiliations
- Departments of aGynecologic Oncology,
- Memorial Sloan Kettering Cancer Center (US)
- Surgical Pathology, and
- Immunology,
- Roswell Park Comprehensive Cancer Center (US)
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2010-04-12
- Volume
- 107
- Issue
- 17
- Pages
- 7875-7880
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC2867907
- OpenAlex
- W2041143310
- Cited by
- 859
- References
- 24
- Citations by year
- 2026: 25 · 2025: 31 · 2024: 54 · 2023: 76 · 2022: 78 · 2021: 78 · 2020: 87 · 2019: 73 · 2018: 54 · 2017: 77 · 2016: 53 · 2015: 57 · 2014: 29 · 2013: 32 · 2012: 24
- FWCI
- 13.58
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Cancer Research Institute
- Ovarian Cancer Research Fund
- Ludwig Institute for Cancer Research
- 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
- NY-ESO-1, cancer-testis antigens, epithelial ovarian cancer, tumor-infiltrating lymphocytes, tumor-associated lymphocytes, CD8+ T cells, LAG-3, PD-1, inhibitory receptors, T cell exhaustion, tumor immune tolerance, IL-10, interleukin-6, tumor ascites, T cell receptor gene usage, dual blockade, antitumor immunity
- MeSH terms
- Lymphocyte Activation Gene 3 Protein, Antibodies, Monoclonal, Antigens, Neoplasm, Enzyme-Linked Immunosorbent Assay, Female, Humans, Membrane Proteins, Ovarian Neoplasms, Signal Transduction, Antigens, CD, Gene Expression Regulation, Neoplastic, Cytokines, Lymphocytes, Tumor-Infiltrating, CD8-Positive T-Lymphocytes, Apoptosis Regulatory Proteins, Programmed Cell Death 1 Receptor
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