Upregulation of Tim-3 and PD-1 expression is associated with tumor antigen-specific CD8+ T cell dysfunction in melanoma patients
Open accessAbstract
The paradoxical coexistence of spontaneous tumor antigen–specific immune responses with progressive disease in cancer patients furthers the need to dissect the molecular pathways involved in tumor-induced T cell dysfunction. In patients with advanced melanoma, we have previously shown that the cancer-germline antigen NY-ESO-1 stimulates spontaneous NY-ESO-1–specific CD8+ T cells that up-regulate PD-1 expression. We also observed that PD-1 regulates NY-ESO-1–specific CD8+ T cell expansion upon chronic antigen stimulation. In the present study, we show that a fraction of PD-1+ NY-ESO-1–specific CD8+ T cells in patients with advanced melanoma up-regulates Tim-3 expression and that Tim-3+PD-1+ NY-ESO-1–specific CD8+ T cells are more dysfunctional than Tim-3−PD-1+ and Tim-3−PD-1− NY-ESO-1–specific CD8+ T cells, producing less IFN-γ, TNF, and IL-2. Tim-3–Tim-3L blockade enhanced cytokine production by NY-ESO-1–specific CD8+ T cells upon short ex vivo stimulation with cognate peptide, thus enhancing their functional capacity. In addition, Tim-3–Tim-3L blockade enhanced cytokine production and proliferation of NY-ESO-1–specific CD8+ T cells upon prolonged antigen stimulation and acted in synergy with PD-1–PD-L1 blockade. Collectively, our findings support the use of Tim-3–Tim-3L blockade together with PD-1–PD-L1 blockade to reverse tumor-induced T cell exhaustion/dysfunction in patients with advanced melanoma.
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High expression of Tim-3, CD57, and KLRG-1, in addition to low CD28, is thought to be associated with T cell senescence.
“In addition to low expression of CD28, high expression of Tim-3, CD57, killer cell lectin-like receptor subfamily G, member 1 (KLRG-1) are thought to be associated with T cell senescence [40,60–64](Fig. 2).”
From T cell anergy, exhaustion, senescence, and stemness in the tumor microenvironment (2013) · cites this paper as [63]
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- Authors
- Fourcade, J., Sun, Z., Benallaoua, M., Guillaume, P., Luescher, I. F., Sander, C., Kirkwood, J. M., Kuchroo, V., & Zarour, H. M.
- Affiliations
- University of Pittsburgh (US)
- Ludwig Cancer Research (CH)
- Brigham and Women's Hospital (US)
- Corresponding author
- Zarour, Hassane M.
- ORCID
- Venue
- Journal of Experimental Medicine
- Publisher
- Rockefeller University Press
- Published
- 2010-09-06
- Volume
- 207
- Issue
- 10
- Pages
- 2175-2186
- ISSN
- 0022-1007 (ISSN-L)
- 1540-9538
- PMC
- PMC2947081
- OpenAlex
- W2149121521
- Cited by
- 1,307
- References
- 20
- Citations by year
- 2026: 45 · 2025: 59 · 2024: 72 · 2023: 82 · 2022: 85 · 2021: 110 · 2020: 126 · 2019: 105 · 2018: 109 · 2017: 109 · 2016: 86 · 2015: 92 · 2014: 64 · 2013: 67 · 2012: 59
- FWCI
- 25.58
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The Journal of Experimental Medicine (publishedVersion)
- PubMed Central (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- IRIS (submittedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- SERVAL (Université de Lausanne) (submittedVersion, other-oa)
- Funders
- Cancer Research Institute
- University of Pittsburgh
- National Institutes of Health (UL1TR000005)
- National Cancer Institute (R01 CA90360, R01CA090360, R01CA112198, R01CA157467)
- National Center for Advancing Translational Sciences
- 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
- TIM-3, PD-1, PD-L1, melanoma, NY-ESO-1, T cell exhaustion, T cell dysfunction, PD-1/PD-L1 blockade, cytokine production, cancer immunotherapy
- MeSH terms
- Hepatitis A Virus Cellular Receptor 2, Antigens, Neoplasm, Humans, Immunity, Cellular, Interferon-gamma, Interleukin-2, Melanoma, Membrane Proteins, Tumor Necrosis Factor-alpha, Antigens, CD, Up-Regulation, CD8-Positive T-Lymphocytes, Epitopes, T-Lymphocyte, Apoptosis Regulatory Proteins, Programmed Cell Death 1 Receptor
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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