Targeting CD39 in Cancer Reveals an Extracellular ATP- and Inflammasome-Driven Tumor Immunity

Area of Science:

• Immunology
• Cancer Biology
• Pharmacology

Background:

• CD39 enzyme converts extracellular ATP (eATP) to AMP, influencing immune responses.
• Adenosine signaling is a key target in cancer immunotherapy.
• The precise mechanism of CD39 antibodies is not fully elucidated.

Purpose of the Study:

• To investigate the mechanism of action of CD39 antibodies.
• To contrast anti-CD39 monoclonal antibodies (mAbs) with other adenosinergic pathway agents.
• To elucidate the role of eATP-P2X7-inflammasome-IL18 axis in anti-CD39 efficacy.

Main Methods:

• Utilized syngeneic and humanized tumor models.
• Assessed anti-CD39 monoclonal antibody (mAb) potency and mechanism.
• Analyzed coexpression of CD39 and P2X7 on myeloid cells, IL18 release, and T-cell expansion.

Main Results:

• CD39 blockade activates an eATP-P2X7-ASC-NALP3-inflammasome-IL18 pathway for antitumor activity.
• Efficacy correlated with CD39/P2X7 coexpression, macrophage depletion, and IL18 release.
• Anti-CD39 antibodies promoted T-cell infiltration, overcame anti-PD-1 resistance, and enhanced T-cell function in human models.

Conclusions:

• Antibodies blocking CD39 trigger a novel eATP-P2X7-inflammasome-IL18 axis.
• This pathway reduces macrophages, boosts T-cell function, and overcomes immunotherapy resistance.
• Anti-CD39 therapy holds potential for enhancing adoptive T-cell transfer efficacy.