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TLR8 signaling enhances tumor immunity by preventing tumor‐induced T‐cell senescence
Open accessAbstract
Accumulating evidence suggests the immunosuppressive microenvironments created by malignant tumors represent a major obstacle for effective anti‐tumor immunity. A better understanding of the suppressive mechanisms mediated by tumor microenvironments and the development of strategies to reverse the immune suppression are major challenges for the success of tumor immunotherapy. Here, we report that human tumor cells can induce senescence in naïve/effector T cells, exhibiting potent suppressive function in vitro and in vivo . We further show that tumor‐derived endogenous cyclic adenosine monophosphate (cAMP) is responsible for the induction of T‐cell senescence. Importantly, activation of TLR8 signaling in tumor cells can block the induction and reverse the suppression of senescent naïve and tumor‐specific T cells in vitro and in vivo , resulting in enhanced anti‐tumor immunity. These studies identify a novel mechanism of human tumor‐mediated immune suppression and provide a new strategy to reverse tumor immunosuppressive effects for tumor immunotherapy.
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“Furthermore, the activation of Toll-like receptor 8 signaling in tumor cells can enhance antitumor immunity by blocking the induction of senescent T cells and tumor-specific T cells in vitro and in vivo and reversing their inhibitory effect [63].”
From Immunosenescence: a key player in cancer development (2020) · cites this paper as [63]
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“In addition, tumor cells activate the PKA-CREB and P38 pathways by producing cAMP, thereby causing DNA damage and senescence of T cells [51, 53, 58–63].”
From Immunosenescence: a key player in cancer development (2020) · cites this paper as [63]
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Metadata
- Authors
- Ye, J., Ma, C., Hsueh, E. C., Dou, J., Mo, W., Liu, S., Han, B., Huang, Y., Zhang, Y., Varvares, M. A., Hoft, D. F., & Peng, G.
- Affiliations
- Saint Louis University (US)
- Corresponding author
- Peng, Guangyong
- ORCID
- Venue
- EMBO Molecular Medicine
- Published
- 2014-09-17
- Volume
- 6
- Issue
- 10
- Pages
- 1294-1311
- ISSN
- 1757-4676 (ISSN-L)
- 1757-4684
- PMC
- PMC4287933
- OpenAlex
- W2000656984
- Cited by
- 161
- References
- 56
- Citations by year
- 2026: 6 · 2025: 24 · 2024: 24 · 2023: 14 · 2022: 16 · 2021: 27 · 2020: 22 · 2019: 6 · 2018: 13 · 2017: 5 · 2016: 1 · 2015: 3
- FWCI
- 1.37
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- EMBO Molecular Medicine (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- American Cancer Society (RSG‐10‐160‐01‐LIB)
- Melanoma Research Alliance
- National Institutes of Health
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Keywords
- T cell senescence, tumor immunosuppression, tumor microenvironment, cyclic AMP, antitumor immunity, cancer immunotherapy, tumor-specific T cells
- MeSH terms
- Cyclic AMP, Animals, Cells, Cultured, Flow Cytometry, Humans, Neoplasms, T-Lymphocytes, Blotting, Western, Signal Transduction, CD4-Positive T-Lymphocytes, Immunotherapy, Adoptive, Mice, SCID, Mice, Inbred NOD, Cellular Senescence, Mice, Knockout, Coculture Techniques, Xenograft Model Antitumor Assays, RNA Interference, Cell Line, Tumor, Toll-Like Receptor 8, Interleukin Receptor Common gamma Subunit, Tumor Microenvironment, MCF-7 Cells
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