The DOI matches its Crossref record; 59 of the 60 references it cites were found in a registry or an index.
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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Cites
PD-1 and PD-L1 Immune Checkpoint Blockade to Treat Breast Cancer
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“…studies have demonstrated that blocking inhibitory receptors (checkpoint blockade) can mediate functional rescue of unresponsive T cells in chronic infection or tumors (Barber et al., 2006; Brahmer et al., 2012; Perez-Gracia et al., 2014; (A) Tamoxifen (Tam)-inducible ASTxCre-ERT2 tumor model.”
Mutational landscape determines sensitivity to PD-1 blockade in non–small cell lung cancer
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Genetic Basis for Clinical Response to CTLA-4 Blockade in Melanoma
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Cited by
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Understanding the tumor immune microenvironment (TIME) for effective therapy
Binnewies, M., Roberts, E. W., Kersten, K., Chan, V., Fearon, D. F., Merad, M., Coussens, L. M., Gabrilovich, D. I., Ostrand-Rosenberg, S., Hedrick, C. C., et al. (2018) · Nature Medicine · doi:10.1038/s41591-018-0014-x · Cited by 6,145
Signatures of T cell dysfunction and exclusion predict cancer immunotherapy response
Jiang, P., Gu, S., Pan, D., Fu, J., Sahu, A., Hu, X., Li, Z., Traugh, N., Bu, X., Li, B., et al. (2018) · Nature Medicine · doi:10.1038/s41591-018-0136-1 · Cited by 5,179
The evolving landscape of biomarkers for checkpoint inhibitor immunotherapy
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Miller, B. C., Sen, D. R., Al Abosy, R., Bi, K., Virkud, Y. V., LaFleur, M. W., Yates, K. B., Lako, A., Felt, K., Naik, G. S., et al. (2019) · Nature Immunology · doi:10.1038/s41590-019-0312-6 · Cited by 2,087
CD8 T Cell Exhaustion During Chronic Viral Infection and Cancer
McLane, L. M., Abdel-Hakeem, M. S., & Wherry, E. J. (2019) · Annual Review of Immunology · doi:10.1146/annurev-immunol-041015-055318 · Cited by 2,054
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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