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Co-inhibition of CD73 and A2AR Adenosine Signaling Improves Anti-tumor Immune Responses
Arabella Young1, Shin Foong Ngiow1, Deborah S Barkauskas2
1Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, 300 Herston Road, Herston, QLD 4006, Australia; School of Medicine, The University of Queensland, Herston, QLD 4006, Australia.
Abstract:
Preclinical studies targeting the adenosinergic pathway have gained much attention for their clinical potential in overcoming tumor-induced immunosuppression. Here, we have identified that co-blockade of the ectonucleotidase that generates adenosine CD73 and the A2A adenosine receptor (A2AR) that mediates adenosine signaling in leuokocytes, by using compound gene-targeted mice or therapeutics that target these molecules, limits tumor initiation, growth, and metastasis. This tumor control requires effector lymphocytes and interferon-γ, while antibodies targeting CD73 promote an optimal therapeutic response in vivo when engaging activating Fc receptors. In a two-way mixed leukocyte reaction using a fully human anti-CD73, we demonstrated that Fc receptor binding augmented the production of proinflammatory cytokines.
Insights
Blocking CD73 and the A2A adenosine receptor (A2AR) limits tumor growth and spread. This approach, requiring effector lymphocytes and interferon-gamma, enhances anti-tumor immunity and cytokine production for improved cancer therapy.
Area of Science:
- Immunology
- Oncology
- Pharmacology
Background:
- The adenosinergic pathway plays a crucial role in tumor-induced immunosuppression.
- Targeting this pathway offers potential for cancer treatment.
Purpose of the Study:
- To investigate the combined blockade of CD73 and the A2A adenosine receptor (A2AR) for cancer therapy.
- To evaluate the efficacy of this co-blockade in limiting tumor initiation, growth, and metastasis.
Main Methods:
- Utilized compound gene-targeted mice and specific therapeutics targeting CD73 and A2AR.
- Assessed tumor control, requirement for effector lymphocytes and interferon-gamma.
- Investigated the role of Fc receptor engagement with anti-CD73 antibodies in vivo.
- Performed a two-way mixed leukocyte reaction with a human anti-CD73 antibody.
Main Results:
- Co-blockade of CD73 and A2AR effectively limited tumor initiation, growth, and metastasis.
- Tumor control was dependent on effector lymphocytes and interferon-gamma.
- Anti-CD73 antibodies enhanced therapeutic response via Fc receptor engagement.
- Fc receptor binding augmented proinflammatory cytokine production.
Conclusions:
- Combined blockade of CD73 and A2AR is a promising strategy to overcome tumor-induced immunosuppression.
- This approach enhances anti-tumor immunity and may improve therapeutic outcomes in cancer.
