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Cited by 218Adenosine and Purinergic SignalingCancer Immunotherapy and BiomarkersBiochemical and Molecular Research

Hostile, Hypoxia–A2-Adenosinergic Tumor Biology as the Next Barrier to Overcome for Tumor Immunologists

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Sitkovsky, Michail V., Hatfield, Stephen, Abbott, Robert, Belikoff, Bryan, Lukashev, Dmitriy, Ohta, Akio·2014·Cancer Immunology Research
DOI 10.1158/2326-6066.cir-14-0075PMC PMC4331061
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Abstract

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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  • The net effect of systemic HIF inhibition in HCC is to relieve immunosuppression by increasing the recruitment of CD8+ T cells and NK cells to the tumor.

    “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]

    The Introduction describes HIF-1α as immunosuppressive, and the Conclusions and expectations propose targeting the hypoxia–adenosine pathway to prevent inhibition of antitumor T and NK cells (page numbers unavailable). The paper does not establish that systemic HIF inhibition in HCC increases recruitment of CD8+ T cells or NK cells to tumors; that mechanism and setting go beyond its prediction. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • Hypoxia induces increased expression of CD73, which mediates production of extracellular adenosine, which binds adenosine 2A receptors on T lymphocytes and NK cells, thereby suppressing antitumor immunity.

    “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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2 retracted

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Research works printed but not linked: 2

  1. [13]Sitkovsky MV Lukashev D Apasov S Physiological control of immune response and inflammatory tissue damage by hypoxia-inducible factors and adenosine A2A receptors Annu Rev Immunol 2004 22 657 82 15032592
  2. [70]Jin D Fan J Wang L CD73 on tumor cells impairs antitumor T-cell responses: a novel mechanism of tumor-induced immune suppression Cancer Res 2010 70 2245 55 20179192 PMC2883609

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Authors
Sitkovsky, M. V., Hatfield, S., Abbott, R., Belikoff, B., Lukashev, D., & Ohta, A.
Affiliations
Northeastern University (US)
Corresponding author
Sitkovsky, Michail V.
ORCID
Venue
Cancer Immunology Research
Publisher
American Association for Cancer Research (AACR)
Published
2014-07-01
Volume
2
Issue
7
Pages
598-605
ISSN
  • 2326-6066 (ISSN-L)
  • 2326-6074
DOI
10.1158/2326-6066.cir-14-0075
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
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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