CD73 inhibition overcomes adaptive immune resistance to PARP inhibition in models of prostate cancer
Ping Xie, Renqiang Ma, Minghui Zhang, Jie Fan, Hui Tang, Longzhen Song, Yong Wan, Timothy M. Kuzel, Deyu Fang, Weiguo Cui, Jennifer D. Wu, Sarki A. Abdulkadir, Yi Zhang, Akash Patnaik, Bin Zhang
Ping Xie, Renqiang Ma, Minghui Zhang, Jie Fan, Hui Tang, Longzhen Song, Yong Wan, Timothy M. Kuzel, Deyu Fang, Weiguo Cui, Jennifer D. Wu, Sarki A. Abdulkadir, Yi Zhang, Akash Patnaik, Bin Zhang
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Research Article Immunology Oncology

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.

Authors

Ping Xie, Renqiang Ma, Minghui Zhang, Jie Fan, Hui Tang, Longzhen Song, Yong Wan, Timothy M. Kuzel, Deyu Fang, Weiguo Cui, Jennifer D. Wu, Sarki A. Abdulkadir, Yi Zhang, Akash Patnaik, Bin Zhang

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Figure 3

PARPi upregulates CD73 expression through the TGF-β/AKT signaling axis.

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PARPi upregulates CD73 expression through the TGF-β/AKT signaling axis. ...
(A) Heatmap presenting DEGs related to the TGF-β pathway in olaparib-treated MycCaP cells relative to control. (B) RT-qPCR measurement of Tgf-b1 mRNA levels in MycCaP and MycCaP-PTEN–KO cells treated with 10 or 20 μM olaparib. (C) Flow cytometry analysis of pSMAD2 levels in MycCaP cells following olaparib treatment with or without a TGF-β inhibitor. (D) Flow cytometry assessment of CD73 expression in MycCaP cells treated with olaparib in the presence or absence of a TGF-β inhibitor. (E) Western blot analysis of pAKT levels in MycCaP cells treated with olaparib at indicated concentrations. (F) Flow cytometry analysis of CD73 expression in cells pretreated with an AKT inhibitor for 30 minutes before olaparib exposure. (G) Flow cytometry measurement of pAKT levels in MycCaP cells treated with olaparib with or without a TGF-β inhibitor. (H) Flow cytometry analysis of CD73 expression in MycCaP cells treated with olaparib in combination with a TGF-β inhibitor, an AKT inhibitor, or both. (I) ChIP assay showing SP1 binding to the Nt5e promoter in treated MycCaP cells. (J) Flow cytometry assessment of CD73 expression in MycCaP cells treated with or without olaparib in the absence or presence of a TGF-β inhibitor, an ATR inhibitor, or both. Results are representative of 2 (B and G) or 3 (C–F and H–J) independent experiments. Data were analyzed by 1-way ANOVA (B and E) or 2-way ANOVA (C, D, and F–J). Data plotted are mean ± SEM from biological replicates. *P < 0.05, **P < 0.01, ***P < 0.001.