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Hostile, Hypoxia–A2-Adenosinergic Tumor Biology as the Next Barrier to Overcome for Tumor Immunologists
Open accessAbstract
Hypoxia-driven, A2A adenosine receptor (A2AR)–mediated (hypoxia–A2-adenosinergic), T-cell–autonomous immunosuppression was first recognized as critical and nonredundant in protecting normal tissues from inflammatory damage and autoimmunity. However, this immunosuppressive mechanism can be highjacked by bacteria and tumors to provide misguided protection for pathogens and cancerous tissues. Inhibitors of the hypoxia–A2-adenosinergic pathway represent a conceptually novel type of immunologic coadjuvants that could be combined with cancer vaccines, adoptive cell transfer, and/or blockade of negative immunologic regulators to further prolong patient survival and to minimize treatment-related side effects. In support of this approach are preclinical studies and findings that some human cancers are resistant to chemotherapies and immunotherapies due to the tumor-generated extracellular adenosine and A2AR on antitumor T and natural killer (NK) cells. Among the coadjuvants are (i) antagonists of A2AR, (ii) extracellular adenosine-degrading drugs, (iii) inhibitors of adenosine generation by CD39/CD73 ectoenzymes, and (iv) inhibitors of hypoxia–HIF-1α signaling. Combining these coadjuvants with CTLA-4 and/or PD-1 blockade is expected to have additive or even synergistic effects of targeting two different antitumor protective mechanisms. It is expected that even after multicombinatorial blockade of negative immunologic regulators, the antitumor T and NK cells would still be vulnerable to inhibition by hypoxia and A2AR. Yet to be tested is the potential capacity of coadjuvants to minimize the side effects of CTLA-4 and/or PD-1 blockade by decreasing the dose of blocking antibodies or by eliminating the need for dual blockade. Cancer Immunol Res; 2(7); 598–605. ©2014 AACR.
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“Thus, the net effect of systemic HIF inhibition in HCC is to relieve immunosuppression, as predicted (36), by increasing the recruitment of CD8+ T cells and NK cells to the tumor.”
From HIF inhibitor 32-134D eradicates murine hepatocellular carcinoma in combination with anti-PD1 therapy (2022) · cites this paper as [36]
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“hypoxia induces increased expression of CD73, the enzyme that mediates production of extracellular adenosine, which binds to adenosine 2A receptors on T lymphocytes and natural killer (NK) cells, thereby suppressing antitumor immunity (13, 17, 36).”
From HIF inhibitor 32-134D eradicates murine hepatocellular carcinoma in combination with anti-PD1 therapy (2022) · cites this paper as [36]
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Metadata
- Authors
- Sitkovsky, M. V., Hatfield, S., Abbott, R., Belikoff, B., Lukashev, D., & Ohta, A.
- Affiliations
- Northeastern University (US)
- Corresponding author
- Sitkovsky, Michail V.
- Venue
- Cancer Immunology Research
- Published
- 2014-07-01
- Volume
- 2
- Issue
- 7
- Pages
- 598-605
- ISSN
- 2326-6066 (ISSN-L)
- 2326-6074
- PMC
- PMC4331061
- OpenAlex
- W2086437277
- Cited by
- 215
- References
- 82
- Citations by year
- 2026: 9 · 2025: 14 · 2024: 13 · 2023: 29 · 2022: 20 · 2021: 26 · 2020: 29 · 2019: 16 · 2018: 17 · 2017: 11 · 2016: 14 · 2015: 14 · 2014: 2
- FWCI
- 1.64
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Cancer Immunology Research (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- National Cancer Institute (R01CA111985)
- National Institute of General Medical Sciences (R01GM097320)
- National Institute of Allergy and Infectious Diseases (U19AI091693)
- 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 › Molecular Biology › Biochemical and Molecular Research
- Keywords
- tumor hypoxia, adenosine A2A receptor, extracellular adenosine, immunosuppression, HIF-1α signaling, CTLA-4 blockade, anti-PD-1 therapy, cancer vaccines, adoptive cell transfer, natural killer cells, tumor immunology
- MeSH terms
- Humans, Immune Tolerance, Immunotherapy, Neoplasms, T-Lymphocytes, Signal Transduction, Cell Hypoxia, Receptor, Adenosine A2A, Hypoxia-Inducible Factor 1, alpha Subunit
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