CD73 inhibition overcomes adaptive immune resistance to PARP inhibition in models of prostate cancer

Abstract

Metastatic castration-resistant prostate cancer (mCRPC) remains a leading cause of cancer-related mortality in men. Although poly(ADP-ribose) polymerase (PARP) inhibitors are approved for mCRPC patients with homologous recombination repair (HRR) deficiencies, clinical trials combining olaparib with PD-1/PD-L1 inhibitors showed limited efficacy in unselected populations. To investigate the immunomodulatory effects of PARP inhibitors in an unbiased manner, we performed bulk RNA-seq on HRR-proficient MycCaP cells treated with the PARP inhibitor olaparib versus vehicle control. Transcriptomic analysis revealed robust upregulation of CD73 (NT5E), an ectoenzyme and emerging immune checkpoint that generates extracellular adenosine, suggesting an adaptive mechanism that undermines olaparib efficacy and promotes immunosuppression. CD73 induction by olaparib was validated in human and mouse prostate cancer cell lines, with more pronounced effects in HRR-compromised PTEN-KO cells. Mechanistically, olaparib-driven CD73 expression was mediated through DNA damage–activated ATR/CHEK1/IRF1 and TGF-β1/AKT signaling pathways. In parallel, olaparib enhanced tumor immunogenicity by activating type I IFN signaling and antigen presentation machinery. In vivo, combining olaparib with CD73 blockade significantly delayed tumor growth, improved T cell infiltration, and augmented CD8+ T cell effector function across HRR-proficient and PTEN-KO prostate cancer models. These findings identify olaparib-induced CD73 upregulation as an adaptive resistance mechanism and support olaparib plus CD73 blockade as a promising therapeutic strategy for advanced prostate cancer, irrespective of HRR status.