PARP inhibitors restore NK cell function via secretory crosstalk with tumor cells in prostate cancer

Area of Science:

• Oncology
• Immunology
• Molecular Biology

Background:

• Prostate cancer (PCa) is a leading cause of cancer death in men.
• PARP inhibitors (PARPi) treat PCa with BRCA1/2 mutations.
• Mechanisms of PARPi efficacy beyond BRCA mutations are unclear.

Purpose of the Study:

• Investigate how PARPi impact natural killer (NK) cell function in PCa.
• Elucidate the molecular pathways involved in PARPi-mediated NK cell activation.
• Explore novel therapeutic strategies combining PARPi with immunotherapy.

Main Methods:

• Assessed NK cell function in response to PARPi treatment.
• Measured cyclophilin A (CypA) secretion from PCa cells.
• Investigated CypA binding to ANXA6 and downstream signaling (FPR1-AKT pathway).
• Evaluated therapeutic efficacy of combined PARPi and NK cell therapy in mouse models.

Main Results:

• PARPi restored NK cell function by promoting CypA secretion from PCa cells.
• Tumor-derived CypA activates NK cells via ANXA6 and FPR1 signaling.
• CypA inhibition abrogated PARPi efficacy by blocking NK cell activation.
• Combination therapy of PARPi and NK cell transfer significantly improved survival in preclinical models.

Conclusions:

• PARPi induce a secretory crosstalk between PCa cells and NK cells.
• CypA-FPR1-AKT pathway is crucial for PARPi-mediated NK cell activation.
• Combining PARPi with NK cell therapy is a promising strategy for PCa treatment.