The DOI matches its Crossref record; 59 of the 60 references it cites were found in a registry or an index.
Clonal Deletion of Tumor-Specific T Cells by Interferon-γ Confers Therapeutic Resistance to Combination Immune Checkpoint Blockade
Open accessAbstract
Resistance to checkpoint-blockade treatments is a challenge in the clinic. We found that although treatment with combined anti-CTLA-4 and anti-PD-1 improved control of established tumors, this combination compromised anti-tumor immunity in the low tumor burden (LTB) state in pre-clinical models as well as in melanoma patients. Activated tumor-specific T cells expressed higher amounts of interferon-γ (IFN-γ) receptor and were more susceptible to apoptosis than naive T cells. Combination treatment induced deletion of tumor-specific T cells and altered the T cell repertoire landscape, skewing the distribution of T cells toward lower-frequency clonotypes. Additionally, combination therapy induced higher IFN-γ production in the LTB state than in the high tumor burden (HTB) state on a per-cell basis, reflecting a less exhausted immune status in the LTB state. Thus, elevated IFN-γ secretion in the LTB state contributes to the development of an immune-intrinsic mechanism of resistance to combination checkpoint blockade, highlighting the importance of achieving the optimal magnitude of immune stimulation for successful combination immunotherapy strategies.
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“in mouse models of colon and prostate cancer, combined administration of anti-CTLA4 and anti-PD-1 antibodies in the low tumour burden state (following resection of the primary tumour) provided improved control of established tumours but compromised antitumour immunity109.”
From Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma (2024) · cites this paper as [109]
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“This impaired response was attributed to IFNγ-mediated depletion of tumour-reactive T cells owing to activation-induced cell death.”
From Adjuvant and neoadjuvant immunotherapies in hepatocellular carcinoma (2024) · cites this paper as [109]
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Metadata
- Authors
- Pai, C.-C. S., Huang, J. T., Lu, X., Simons, D. M., Park, C., Chang, A., Tamaki, W., Liu, E., Roybal, K. T., Seagal, J., Chen, M., Hagihara, K., Wei, X. X., DuPage, M., Kwek, S. S., Oh, D. Y., Daud, A., Tsai, K. K., Wu, C., Zhang, L., Fasso, M., Sachidanandam, R., Jayaprakash, A., Lin, I., Casbon, A.-J., Kinsbury, G. A., & Fong, L.
- Affiliations
- University of California, San Francisco (US)
- AbbVie (United States) (US)
- The University of Texas Southwestern Medical Center (US)
- Corresponding author
- Fong, Lawrence
- ORCID
- Venue
- Immunity
- Publisher
- Elsevier BV
- Published
- 2019-02
- Volume
- 50
- Issue
- 2
- Pages
- 477-492.e8
- ISSN
- 1074-7613 (ISSN-L)
- PMC
- PMC6886475
- OpenAlex
- W2913142277
- Cited by
- 141
- References
- 60
- Citations by year
- 2026: 10 · 2025: 20 · 2024: 18 · 2023: 18 · 2022: 18 · 2021: 26 · 2020: 17 · 2019: 14
- FWCI
- 7.84
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Immunity (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- Bristol-Myers Squibb
- AbbVie
- National Cancer Institute (R01CA163012, R01CA194511, U01CA233100)
- Prostate Cancer Foundation
- 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
- interferon-gamma, immune checkpoint blockade, anti-CTLA-4, anti-PD-1, combination immunotherapy, tumor-specific T cells, clonal deletion, T cell apoptosis, IFN-gamma receptor, T cell exhaustion, T cell receptor repertoire, low tumor burden, melanoma, immunotherapy resistance, T cell clonotypes
- MeSH terms
- Animals, Antibodies, Monoclonal, Humans, Interferon-gamma, Male, Mice, Inbred C57BL, Neoplasms, Experimental, T-Lymphocytes, Clonal Deletion, Mice, Knockout, Drug Resistance, Neoplasm, Cell Line, Tumor, Tumor Burden, CTLA-4 Antigen, Programmed Cell Death 1 Receptor
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