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

Abstract

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.

Prostaglandin E2-mediated adenosinergic effects on CD14+cells: Self-amplifying immunosuppression in cancer

“…Human monocytes and macrophages are largely CD73 negative but express CD39. 13 Although CD73 upregulation has been reported on other cell types, such as on T cells, epithelial cells, 30 endothelial cells 18 and murine leukocytes, 17 such an observation has only recently been made on human macrophages in ovarian cancer. 31 We have reported earlier that tumor cells may be present in mesothelioma PE 24 and here we demonstrate that these tumor cells in PE may express CD73 but not CD39.…”

Targeting the adenosine 2A receptor enhances chimeric antigen receptor T cell efficacy

“…Adenosine binds to 4 known receptors: A 1 , A 2A (herein referred to as A 2A R), A 2B , and A 3 . Although A 2B and A 3 are also expressed on T cells, adenosine is thought to predominantly suppress endogenous antitumor T cell responses through stimulation of A 2A Rs expressed on activated T cells (18,23,24,(27)(28)(29)(30)(31). Indeed, A 2A Rdeficient mice (hereafter referred to as A 2A R -/-mice) are resistant to the immunosuppressive effects of adenosine and elicit enhanced antitumor immune responses (18,27,32,33).…”

Role of adenosine in tumor progression: focus on A2B receptor as potential therapeutic target

“…[31] Hypoxia, which is a common feature of the tumor microenvironment that promotes immunosuppression, is one of the main factors responsible of the increased production of adenosine within many solid tumors. [11] Indeed, the expression and the enzymatic activities of CD39 and CD73, responsible of the adenosine generation, increased under hypoxic conditions, while the expression of the adenosine kinase, which inhibits the metabolism of adenosine, is down-regulated. [11] At the same time, the expression of adenosine receptors A 2A and A 2B is also up-regulated.…”

“…Among them, extracellular adenosine, an ATP-derived molecule generated by the extracellular CD39/CD73 enzymes, has been identified as an immune checkpoint that critically impairs the anti-tumor immune response mainly via A 2A adenosine receptor subtype. [10][11][12] Accordingly, selective inhibitors of adenosine signaling pathways have been tested in pre-clinical studies [13,14] and some of them, including the antibody anti-CD73 and the A 2A receptor antagonists are currently in Phase I clinical trials in cancer patients, either as single agents, or in combination with immune checkpoints inhibitors such as anti PD-1 monoclonal antibodies [NCT02503774 and NCT02655822].…”