Tumor-Derived γδ Regulatory T Cells Suppress Innate and Adaptive Immunity through the Induction of Immunosenescence
Open accessAbstract
Fundamentally understanding the suppressive mechanisms used by different subsets of tumor-infiltrating regulatory T (Treg) cells is critical for the development of effective strategies for antitumor immunotherapy. γδ Treg cells have recently been identified in human diseases including cancer. However, the suppressive mechanisms and functional regulations of this new subset of unconventional Treg cells are largely unknown. In the current studies, we explored the suppressive mechanism(s) used by breast tumor-derived γδ Treg cells on innate and adaptive immunity. We found that γδ Treg cells induced immunosenescence in the targeted naive and effector T cells, as well as dendritic cells (DCs). Furthermore, senescent T cells and DCs induced by γδ Treg cells had altered phenotypes and impaired functions and developed potent suppressive activities, further amplifying the immunosuppression mediated by γδ Treg cells. In addition, we demonstrated that manipulation of TLR8 signaling in γδ Treg cells can block γδ Treg–induced conversion of T cells and DCs into senescent cells in vitro and in vivo. Our studies identify the novel suppressive mechanism mediated by tumor-derived γδ Treg cells on innate and adaptive immunity, which should be critical for the development of strong and innovative approaches to reverse the tumor-suppressive microenvironment and improve effects of immunotherapy.
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Many factors in the tumor microenvironment, including cAMP, glucose competition, and oncogenic stress, can induce senescence of T cells, macrophages, natural killer cells, and dendritic cells.
“The role of immunosenescence in tumors is sophisticated: the many factors involved include cAMP, glucose competition, and oncogenic stress in the tumor microenvironment, which can induce the senescence of T cells, macrophages, natural killer cells, and dendritic cells.”
From Immunosenescence: a key player in cancer development (2020) · cites this paper as [52]
An immune system disorder in the elderly may promote tumor growth and induce T cell senescence, such as an increase in the proportion of tumor-associated macrophages and regulatory T cells.
“Multiple studies have shown that an immune system disorder in the elderly may promote tumor growth and induce T cell senescence, such as an increase in the proportion of tumor-associated macrophages and regulatory T cells (Tregs) [51–55].”
From Immunosenescence: a key player in cancer development (2020) · cites this paper as [52]
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- Authors
- Ye, J., Ma, C., Hsueh, E. C., Eickhoff, C. S., Zhang, Y., Varvares, M. A., Hoft, D. F., & Peng, G.
- Affiliations
- Saint Louis University (US)
- Shandong Medical College (CN)
- Corresponding author
- Ye, Jian
- Ma, Chunling
- Peng, Guangyong
- ORCID
- Venue
- The Journal of Immunology
- Publisher
- Oxford University Press (OUP)
- Published
- 2013-03-01
- Volume
- 190
- Issue
- 5
- Pages
- 2403-2414
- ISSN
- 0022-1767 (ISSN-L)
- 1550-6606
- PMC
- PMC3578061
- OpenAlex
- W2109077280
- Cited by
- 203
- References
- 53
- Citations by year
- 2026: 5 · 2025: 20 · 2024: 23 · 2023: 16 · 2022: 22 · 2021: 28 · 2020: 13 · 2019: 13 · 2018: 17 · 2017: 9 · 2016: 6 · 2015: 9 · 2014: 15 · 2013: 7
- FWCI
- 6.82
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- The Journal of Immunology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Allergy and Infectious Diseases (R21AI094478, R21AI097852)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Keywords
- tumor-infiltrating regulatory T cells, immunosenescence, tumor immunosuppression, breast cancer, T cell senescence, cancer immunotherapy, tumor microenvironment
- MeSH terms
- Animals, Breast Neoplasms, Cell Communication, Dendritic Cells, Female, Humans, Immunity, Innate, Tumor Cells, Cultured, Signal Transduction, Gene Expression, Receptors, Antigen, T-Cell, gamma-delta, Cellular Senescence, Mice, Knockout, CD8-Positive T-Lymphocytes, Coculture Techniques, T-Lymphocytes, Regulatory, Toll-Like Receptor 8, Mice, Adaptive Immunity, Tumor Microenvironment
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