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 1

PARPi induces CD73 upregulation in prostate cancer cells, conferring adaptive immune resistance.

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PARPi induces CD73 upregulation in prostate cancer cells, conferring ada...
(A) Reactome pathway analysis of differentially expressed genes (DEGs) from bulk RNA-seq in MycCaP cells treated with olaparib compared with vehicle control, using the DAVID. (B) Olaparib treatment induced DEGs among 45 detected immune checkpoint–related molecules in bulk RNA-seq. (C) RT-qPCR analysis of induced Nt5e expression in MycCaP, MycCaP-PTEN–KO, and DKO cells following olaparib treatment. (D) Flow cytometry analysis of dose-dependent increases in surface CD73 levels following 24 h olaparib treatment in MycCaP, MycCaP-PTEN–KO, and DKO cells. (E) Western blot analysis of CD73 protein expression and quantification in MycCaP and MycCaP-PTEN–KO cells treated with olaparib (0, 10, 20, and 50 μM) for 24 h. (F) GSEA revealing enrichment of antigen-processing/ presentation and type I IFN–related pathways following olaparib treatment. (G) Flow cytometry analysis of MHC-I (H-2Kq) expression in MycCaP and MycCaP-PTEN–KO cells following olaparib treatment. (H) Schematic overview of coculturing pretreated nontargeting control or CD73-KD MycCaP with tumor-reactive CD8+ T cells. (I) Flow cytometry analysis of IFN-γ and TNF-α production, and CD25 expression in cocultured CD8+ T cells. (J) Measurement of tumor cell killing by cocultured CD8+ T cells. NT, nontargeting control. Results are representative of 2 (A–D and J) or 3 (E, G, and I) independent experiments. Data were analyzed by unpaired 2-tailed Student’s t test (B), 1-way ANOVA with Tukey’s post hoc correction (C–E and G), or 2-way ANOVA with Tukey’s post hoc correction (I and J). Data plotted are mean ± SEM from biological replicates. *P < 0.05, **P < 0.01, ***P < 0.001.