Targeting immunosuppressive adenosine in cancer.

Area of Science:

• Oncology
• Immunology
• Pharmacology

Background:

• Immunotherapy resistance, including innate and adaptive resistance, limits the effectiveness of anti-programmed cell death protein 1 (PD1), anti-PD1 ligand 1 (PDL1), and anti-cytotoxic T lymphocyte antigen 4 (CTLA4) therapies in advanced cancers.
• The tumor microenvironment harbors multiple immunosuppressive mechanisms, with the adenosinergic pathway being a significant contributor.
• Hypoxic tumors activate the adenosinergic pathway, leading to extracellular adenosine-mediated suppression through tumor-intrinsic and host-mediated actions.

Purpose of the Study:

• To review the role of the adenosinergic pathway in cancer development and metastasis.
• To discuss the therapeutic potential of targeting components of the adenosinergic pathway.
• To summarize early clinical data on agents inhibiting the adenosinergic pathway.

Main Methods:

• Review of preclinical studies involving adenosine receptor antagonists and antibodies in mouse models.
• Analysis of the mechanisms of action of adenosinergic pathway inhibitors.
• Examination of early-phase clinical trial data for agents targeting the adenosinergic pathway.

Main Results:

• Preclinical studies demonstrate that targeting the adenosinergic pathway can elicit favorable anti-tumor immune responses.
• Agents targeting the adenosinergic pathway are currently in first-in-human clinical trials, both as monotherapies and in combination with anti-PD1/PDL1 agents.
• The complex interplay between adenosine, adenosine receptors, and the tumor microenvironment is crucial for tumor progression.

Conclusions:

• The adenosinergic pathway is a critical immunosuppressive mechanism in cancer, presenting a viable therapeutic target.
• Targeting the adenosinergic pathway holds promise for overcoming resistance to current immunotherapies and improving cancer treatment outcomes.
• Early clinical data suggest the potential efficacy of adenosinergic pathway inhibitors in cancer patients.