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Published on: June 14, 2024
Targeting Hypoxia-A2A Adenosinergic Immunosuppression of Antitumor T Cells During Cancer Immunotherapy
Joseph M Steingold1, Stephen M Hatfield1
1Department of Pharmaceutical Sciences, New England Inflammation and Tissue Protection Institute, Bouvé College of Health Sciences, Northeastern University, Boston, MA, United States.
Abstract:
The blockade of immunological negative regulators offered a novel therapeutic approach that revolutionized the immunotherapy of cancer. Still, a significant portion of patients fail to respond to anti-PD-1/PD-L1 and/or anti-CTLA-4 therapy or experience significant adverse effects. We propose that one of the major reasons that many patients do not respond to this form of therapy is due to the powerful physiological suppression mediated by hypoxia-adenosinergic signaling. Indeed, both inflamed and cancerous tissues are hypoxic and rich in extracellular adenosine, in part due to stabilization of the transcription factor hypoxia-inducible factor 1 alpha (HIF-1α). Adenosine signals through adenosine A2A receptors (A2AR) to suppress anti-tumor and anti-pathogen immune responses. Several classes of anti-hypoxia-A2AR therapeutics have been offered to refractory cancer patients, with A2AR blockers, inhibitors of adenosine-generating enzymes such as CD39 and CD73, and hypoxia-targeting drugs now reaching the clinical stage. Clinical results have confirmed preclinical observations that blockade of the hypoxia-adenosine-A2AR axis synergizes with inhibitors of immune checkpoints to induce tumor rejection. Thus, A2AR blockers provide a new hope for the majority of patients who are nonresponsive to current immunotherapeutic approaches including checkpoint blockade. Here, we discuss the discoveries that firmly implicate the A2AR as a critical and non-redundant biochemical negative regulator of the immune response and highlight the importance of targeting the hypoxia-adenosine-A2AR axis to manipulate anti-pathogen and anti-tumor immune responses.
Insights
Hypoxia-adenosinergic signaling via adenosine A2A receptors (A2AR) suppresses anti-tumor immunity, limiting cancer immunotherapy effectiveness. Targeting this axis offers new hope for patients unresponsive to current treatments.
Area of Science:
- Immunology
- Oncology
- Pharmacology
Background:
- Cancer immunotherapy using checkpoint inhibitors (e.g., anti-PD-1/PD-L1, anti-CTLA-4) has revolutionized treatment but faces challenges with patient response rates and adverse effects.
- Hypoxia and adenosine signaling, particularly through hypoxia-inducible factor 1 alpha (HIF-1α), create an immunosuppressive tumor microenvironment.
- Adenosine, acting via adenosine A2A receptors (A2AR), potently suppresses crucial anti-tumor and anti-pathogen immune responses.
Purpose of the Study:
- To investigate the role of the hypoxia-adenosine-A2AR axis as a key suppressor of anti-tumor immunity.
- To highlight the therapeutic potential of targeting this axis to overcome resistance to current immunotherapies.
- To discuss the implications of A2AR as a critical regulator of immune responses in both cancer and infectious diseases.
Main Methods:
- Review and synthesis of preclinical and clinical data on hypoxia-adenosinergic signaling in cancer.
- Analysis of the mechanisms by which adenosine A2A receptors (A2AR) mediate immune suppression.
- Evaluation of therapeutic strategies targeting the hypoxia-adenosine-A2AR axis, including A2AR blockers and inhibitors of adenosine-generating enzymes (CD39, CD73).
Main Results:
- The hypoxia-adenosine-A2AR axis is a significant factor contributing to non-response in patients undergoing immunotherapy.
- Blockade of the hypoxia-adenosine-A2AR axis synergizes with immune checkpoint inhibitors to promote tumor rejection.
- Emerging therapeutics targeting this axis are entering clinical trials, showing promise for refractory cancer patients.
Conclusions:
- Adenosine A2A receptors (A2AR) are critical, non-redundant negative regulators of immune responses.
- Targeting the hypoxia-adenosine-A2AR axis represents a promising strategy to enhance the efficacy of cancer immunotherapy.
- This approach offers a new therapeutic avenue for the majority of patients who do not respond to existing immunotherapeutic strategies.
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