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Tumor-Specific T Cell Dysfunction Is a Dynamic Antigen-Driven Differentiation Program Initiated Early during Tumorigenesis
Open accessAbstract
CD8(+) T cells recognizing tumor-specific antigens are detected in cancer patients but are dysfunctional. Here we developed a tamoxifen-inducible liver cancer mouse model with a defined oncogenic driver antigen (SV40 large T-antigen) to follow the activation and differentiation of naive tumor-specific CD8(+) T (TST) cells after tumor initiation. Early during the pre-malignant phase of tumorigenesis, TST cells became dysfunctional, exhibiting phenotypic, functional, and transcriptional features similar to dysfunctional T cells isolated from late-stage human tumors. Thus, T cell dysfunction seen in advanced human cancers may already be established early during tumorigenesis. Although the TST cell dysfunctional state was initially therapeutically reversible, it ultimately evolved into a fixed state. Persistent antigen exposure rather than factors associated with the tumor microenvironment drove dysfunction. Moreover, the TST cell differentiation and dysfunction program exhibited features distinct from T cell exhaustion in chronic infections. Strategies to overcome this antigen-driven, cell-intrinsic dysfunction may be required to improve cancer immunotherapy.
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“Profiling adoptively transferred SV40 large T cell antigen (Tag+)–specific CD8+ T cells indicated that Tag+ T cells followed classic signs of exhaustion upon entry into the tumor-bearing livers (fig. S2D) (19).”
From Bile acid synthesis impedes tumor-specific T cell responses during liver cancer (2025) · cites this paper as [19]
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“Conversely, terminal Tex (Ttex) cells accumulate over time and respond poorly to ICB therapies8,11–13.”
From Proteotoxic stress response drives T cell exhaustion and immune evasion (2025) · cites this paper as [13]
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“Indeed, the T cell immune response to HCC antigens is reportedly dysfunctional and unreactive to HCC55.”
From Tumor-specific cholinergic CD4+ T lymphocytes guide immunosurveillance of hepatocellular carcinoma (2023) · cites this paper as [55]
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Metadata
- Authors
- Schietinger, A., Philip, M., Krisnawan, V. E., Chiu, E. Y., Delrow, J. J., Basom, R. S., Lauer, P., Brockstedt, D. G., Knoblaugh, S. E., Hämmerling, G. J., Schell, T. D., Garbi, N., & Greenberg, P. D.
- Affiliations
- Memorial Sloan Kettering Cancer Center (US)
- University of Washington (US)
- Fred Hutch Cancer Center (US)
- Aduro BioTech (United States) (US)
- German Cancer Research Center (DE)
- Pennsylvania State University (US)
- University of Bonn (DE)
- Corresponding author
- Schietinger, Andrea
- Greenberg, Philip D.
- ORCID
- Venue
- Immunity
- Publisher
- Elsevier BV
- Published
- 2016-08
- Volume
- 45
- Issue
- 2
- Pages
- 389-401
- ISSN
- 1074-7613 (ISSN-L)
- PMC
- PMC5119632
- OpenAlex
- W2514996992
- Cited by
- 720
- References
- 60
- Citations by year
- 2026: 45 · 2025: 77 · 2024: 93 · 2023: 84 · 2022: 78 · 2021: 103 · 2020: 99 · 2019: 61 · 2018: 50 · 2017: 25 · 2016: 5
- FWCI
- 25.49
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Immunity (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (R00CA172371, K99CA172371, K08CA158069, R01CA033084, P30CA008748, P30CA015704)
- National Institute of Allergy and Infectious Diseases (R21AI107776)
- 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
- tumor-specific T cells, CD8+ T cell dysfunction, carcinogenesis, SV40 large T antigen, liver cancer, T cell differentiation, T cell exhaustion, cancer immunotherapy
- MeSH terms
- Animals, Antigens, Polyomavirus Transforming, Cell Differentiation, Cells, Cultured, Disease Models, Animal, Humans, Liver Neoplasms, Lymphocyte Activation, Mice, Inbred C57BL, Mice, Transgenic, Tamoxifen, Immunotherapy, Adoptive, Cellular Senescence, CD8-Positive T-Lymphocytes, Cancer Vaccines, Mice, Tumor Microenvironment, Carcinogenesis
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