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

The hypoxia-driven and A2A or A2B adenosine receptors (A2AR/A2BR)-mediated (“Hypoxia-A2-Adenosinergic”) and T cell autonomous immunosuppression was first recognized as critical and non-redundant in protection of normal tissues from inflammatory damage and autoimmunity. However, this immunosuppressive mechanism is high-jacked by bacteria and tumors to misguidedly protect pathogens and cancerous tissues. The inhibitors of Hypoxia-A2-Adenosinergic pathway represent the conceptually novel type of immunological co-adjuvants to be combined with cancer vaccines, adoptive cell transfer and/or blockade of immunological negative regulators in order to further prolong survival and minimize 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 intracellular cAMP-elevating A2AR and A2BR on anti-tumor T and NK cells. Among co-adjuvants are i) antagonists of A2AR/A2BR; ii) extracellular adenosine-degrading drugs; iii) inhibitors of adenosine generation by CD39/CD73 ecto-enzymes and iv) inhibitors of the hypoxia-HIF-1 alpha signaling. It is emphasized that even after the multi-combinatorial blockade of immunological negative regulators the anti-tumor T and NK cells would be still vulnerable to inhibition by hypoxia and A2AR and A2BR. The advantage of combining these co-adjuvants with the blockade of the CTLA4-A and/or PD-1 is in expectations of additive or even synergistic effects of targeting both immunological and physiological tumor-protecting mechanisms. Yet to be tested is the potential capacity of co-adjuvants to minimize the side effects of blockade of CTLA-4 and/or PD1 by decreasing the dose of blocking antibodies or by eliminating the need in dual blockade.