Hypoxia-Adenosinergic Immunosuppression: Tumor Protection by T Regulatory Cells and Cancerous Tissue Hypoxia
Open accessAbstract
Cancerous tissue protection from tumor-recognizing CD8+ and CD4+ T cells (antitumor T cells) limits the therapeutic potential of immunotherapies. We propose that tumor protection is to a large extent due to (a) inhibition of antitumor T cells by hypoxia-driven accumulation of extracellular adenosine in local tumor microenvironment and due to (b) T regulatory cell-produced extracellular adenosine. The adenosine triggers the immunosuppressive signaling via intracellular cyclic AMP–elevating A2A adenosine receptors (A2AR) on antitumor T cells. In addition, the activated antitumor T cells in hypoxic tumor microenvironment could be inhibited by elevated levels of immunosuppressive hypoxia-inducible factor-1α. Complete rejection or tumor growth retardation was observed when A2AR has been genetically eliminated or antagonized with synthetic drug or with natural A2AR antagonist 1,3,7-trimethylxanthine (caffeine). The promising strategy may be in combining the anti-hypoxia-adenosinergic treatment that prevents inhibition of antitumor T cells by tumor-produced and T regulatory cell-produced adenosine with targeting of other negative regulators, such as CTL antigen-4 blockade. Observations of tumor rejection in mice and massive prospective epidemiologic studies support the feasibility of anti-hypoxia-adenosinergic combined 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 [56]
Tumor-derived endogenous cAMP induces T cell senescence by inhibiting tumor-specific effector T cells in hypoxic microenvironment.
“Several studies have reported that tumor-derived endogenous cyclic adenosine monophosphate (cAMP) induces T cell senescence by inhibiting tumor-specific effector T cells in hypoxic microenvironment [56, 57].”
From Immunosenescence: a key player in cancer development (2020) · cites this paper as [56]
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References 58 · Cited by 253
Research works printed but not linked: 4
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- Authors
- Sitkovsky, M. V., Kjaergaard, J., Lukashev, D., & Ohta, A.
- Affiliations
- Northeastern University (US)
- Authors' Affiliation: New England Inflammation and Tissue Protection Institute, Northeastern University, Boston, Massachusetts
- Venue
- Clinical Cancer Research
- Published
- 2008-09-30
- Volume
- 14
- Issue
- 19
- Pages
- 5947-5952
- ISSN
- 1078-0432 (ISSN-L)
- 1557-3265
- OpenAlex
- W2152701856
- Cited by
- 253
- References
- 58
- Citations by year
- 2026: 6 · 2025: 11 · 2024: 11 · 2023: 20 · 2022: 15 · 2021: 15 · 2020: 16 · 2019: 21 · 2018: 18 · 2017: 16 · 2016: 12 · 2015: 8 · 2014: 17 · 2013: 12 · 2012: 13
- FWCI
- 1.28
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Clinical Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Adenosine and Purinergic Signaling
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Keywords
- tumor hypoxia, extracellular adenosine, adenosine A2A receptor, regulatory T cells, antitumor T cells, immunosuppression, hypoxia-inducible factor-1α, cAMP signaling, caffeine, CTLA-4 blockade, combination immunotherapy, tumor microenvironment, cancer immunotherapy
- MeSH terms
- Adenosine, Animals, Hypoxia, Caffeine, Humans, Immunosuppressive Agents, Immunotherapy, Models, Biological, Neoplasms, T-Lymphocytes, Cytotoxic, CD8-Positive T-Lymphocytes, Receptor, Adenosine A2A, T-Lymphocytes, Regulatory, Mice, Hypoxia-Inducible Factor 1, alpha Subunit
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