A2A Adenosine Receptor Gene Deletion or Synthetic A2A Antagonist Liberate Tumor-Reactive CD8+ T Cells from Tumor-Induced Immunosuppression
Open accessAbstract
Tumor hypoxia–driven accumulation of extracellular adenosine was shown to facilitate tumor evasion by engaging the immunosuppressive, intracellular cAMP-elevating A2 adenosine receptors (A2R) on tumor-reactive effector T cells, but there remains a need for careful evaluation of the limiting factors and properties of A2R blockade–enabled antitumor immunity. In studies of A2AR and/or A2BR gene–deficient mice, we found that A2AR deletion—but not A2BR deletion—liberates endogenous CD8+ T cell antitumor immunity against weakly immunogenic MCA205 sarcomas. Studies of adoptively transferred A2AR−/−, A2BR−/−, or A2AR−/−/A2BR−/− tumor-reactive T cells confirmed that immunosuppression in the tumor microenvironment was mediated by A2AR on CD8+ T cells. Treatment with A2AR antagonist mimicked A2AR gene deletion in adoptive T cell immunotherapy. This therapeutic benefit of targeting A2AR was independent of the anatomical location of tumor growth. The enhanced antitumor reactivity also led to the eradication of established intracranial tumors, which was associated with mouse survival and the maintenance of long-lasting, tumor-specific immunological memory. The blockade of the A2AR on adoptively transferred T cells by synthetic A2AR antagonist led to higher levels of IFN-γ secretion by tumor-infiltrating CD8+ T cells. These data clarify the mechanism of hypoxia-driven immunosuppression in the tumor microenvironment by A2AR on tumor-reactive CD8+ T cells and show that selective A2AR antagonists can be effective in improving the outcomes of T cell–based immunotherapies. Demonstration of the T cell dose dependency of tumor rejection points to a major limitation of current cancer immunotherapies, in which the presence of sufficient numbers of tumor-reactive T cells in a patient is not known.
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Engagement of adenosine 2A receptor with adenosine elicits immunoinhibitory effects: suppressing the activities of tumor-infiltrating CD8+ T cells and hampering the function and differentiation of DCs.
“The engagement of adenosine 2A receptor (A2AR) with adenosine elicits immunoinhibitory effects: suppressing the activities of tumor-infiltrating CD8+ T cells and hampering the function and differentiation of DCs [333, 334].”
From Combination strategies with PD-1/PD-L1 blockade: current advances and future directions (2022) · cites this paper as [334]
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- [35]Sitkovsky M Hatfield S Abbott R Belikoff B Lukashev D Ohta A 2014 Hostile, Hypoxia-A2-Adenosinergic Tumor Biology as the Next Barrier to Overcome for Tumor Immunologists Cancer Immunol Res 7 598 605 PMC4331061 24990240
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- Authors
- Kjaergaard, J., Hatfield, S., Jones, G., Ohta, A., & Sitkovsky, M.
- Affiliations
- New England Inflammation and Tissue Protection Institute, Northeastern University , Boston, MA 02115
- Northeastern University (US)
- Corresponding author
- Hatfield, Stephen
- Ohta, Akio
- Sitkovsky, Michail
- Venue
- The Journal of Immunology
- Publisher
- Oxford University Press (OUP)
- Published
- 2018-07
- Volume
- 201
- Issue
- 2
- Pages
- 782-791
- ISSN
- 0022-1767 (ISSN-L)
- 1550-6606
- PMC
- PMC6052792
- OpenAlex
- W2804340288
- Cited by
- 132
- References
- 60
- Citations by year
- 2026: 8 · 2025: 15 · 2024: 11 · 2023: 11 · 2022: 17 · 2021: 25 · 2020: 26 · 2019: 14 · 2018: 5
- FWCI
- 14.78
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- The Journal of Immunology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (R01CA112561, R01CA111985)
- National Center for Complementary and Integrative Health (R21AT002788)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Adenosine and Purinergic Signaling
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Keywords
- adenosine A2A receptor, adenosine A2B receptor, tumor immunosuppression, CD8+ T cells, tumor hypoxia, extracellular adenosine, adoptive T cell therapy, tumor microenvironment, intracranial tumors, interferon-gamma, cAMP signaling
- MeSH terms
- Adenosine, Animals, Hypoxia, Brain Neoplasms, Disease Models, Animal, Female, Humans, Immune Tolerance, Immunity, Mice, Inbred C57BL, Sarcoma, Immunotherapy, Adoptive, Mice, Knockout, CD8-Positive T-Lymphocytes, Tumor Escape, Receptor, Adenosine A2A, Cell Line, Tumor, Mice, Adenosine A2 Receptor Antagonists, Tumor Microenvironment
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