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

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.