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. 2014 Jul;2(7):598-605.
doi: 10.1158/2326-6066.CIR-14-0075.

Hostile, hypoxia-A2-adenosinergic Tumor Biology as the Next Barrier to Overcome for Tumor Immunologists

Free PMC article

Hostile, hypoxia-A2-adenosinergic Tumor Biology as the Next Barrier to Overcome for Tumor Immunologists

Michail V Sitkovsky et al. Cancer Immunol Res. .
Free PMC article


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.

Conflict of interest statement

Disclosure of potential conflict of interest:

M.V.S. has ownership interests (including patents) in Redoxtherapies, which are charged by the Office of Technology Transfer of the National Institute of Health, USA to translate the developed at NIH technology into medical treatments.


Fig. 1
Fig. 1. The Hypoxia-A2-Adenosinergic immunosuppression, transcription, and redirection of effector functions of anti-pathogen and anti-tumor T cells
Described are the upstream and down-stream stages of this pathway in hypoxic and extracellular adenosine-rich microenvironments of inflamed and cancerous tissues (16). It is believed that the collateral damage to vasculature in inflamed microenvironments by overactive immune cells during the anti-pathogen immune response results in interruption of local blood supply, decrease in local oxygen tension and abnormal local tissue hypoxia (13,18). Tumors are hypoxic because of different reasons that are inflamed tissues i.e. due to the abnormal and chaotic tissue geometry and insufficient vascularization, among others (46). The hypoxia-driven stabilization of Hypoxia Inducible Factor (HIF-1alpha) transcription factor (64) leads to the CD39/CD73 ecto-enzymes-mediated generation of extracellular adenosine (11, 17,20,37,40,44). Adenosine then signals through the Gs protein coupled A2A and A2B adenosine receptors (11,30,31) and triggers the accumulation of intracellular cAMP. The binding of cAMP to the regulatory subunit of cAMP-dependent protein kinase (PKA) results in a cascade of phosphorylation events that inhibits TCR-triggered signaling pathway and therefore inhibits the pro-inflammatory effects of T cells (–29). In addition, the Cyclic AMP Response Element (CRE)-binding protein CREB is participating in transcription of gene products that have CRE after being phosphorylated by PKA (79), while HIF-1alpha is participating in transcription of genes that have the Hypoxia Response Element (HRE) (64). Another immunosuppressive molecule, adenosine A2B receptor was also shown to be regulated by transcriptional activity of HIF-1a (45). The Hypoxia-A2-Adenosinergic transcription may at least partially explain the redirection of immune response and the “infectious” tolerance by Tregs (16). The increased expression of CD73 on the Tregs surface (80) may generate the extracellular adenosine that would further enhance their suppressor activities in an autocrine manner as well as add to the immunosuppressive effects of tumor-produced adenosine on CD8+ T cells in paracrine manner.
Fig. 2
Fig. 2. Fig. 2A. The anti-Hypoxia-A2-Adenosinergic immunotherapeutic co-adjuvants that inhibit the upstream and down-stream stages of the Hypoxia-A2-Adenosinergic pathway.
The shown anti-hypoxia—A2-adenosinergic drugs exist since fortuitously they have been developed for other therapeutic indications. 1) The inhibitors of hypoxia-HIF1 alpha stage –including the inhibitors of HIF-1alpha-can be used in order to weaken the hypoxia and promote the destabilization and degradation of HIF-1alpha in anti-tumor T and NK cells. 2) Blockers or inhibitors of CD39 ecto-ATPase/ADPase and CD73 5′-nucleotidase may be used to prevent the accumulation of extracellular adenosine in TME and thereby decrease the intensity of immunosuppressive signaling through A2AR or A2BR. 3) The commercially available stabilized adenosine deaminase preparations may be tested to degrade the extracellular adenosine. Alternatively, the enzymes such as adenosine kinase may be tested for the ability to decrease the levels of extracellular adenosine by re-phosphorylating it into AMP. 4) Antagonists of A2A adenosine receptor compete with the tissue-produced adenosine for binding to the same binding site of adenosine receptor, but –in contrast to endogenously generated adenosine, antagonists do not activate the A2AR receptor to increase the intracellular cAMP levels.

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