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 6

ST analysis reveals distinct immunocompetent regions associated with combination treatment.

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ST analysis reveals distinct immunocompetent regions associated with com...
(A and B) Visualization of the 10x Genomics Visium results for treated orthotopic MycCaP tumor tissue sections. H&E staining (A) and 13,193 ST spots are presented (B). Treated tissues were clustered via unbiased Louvain clustering (resolution = 0.5), with different colors indicating manually defined CD8+ T cell regions (B, left). The areas with enriched APP signatures are visualized among each sample across clusters (B, right). (C) All 6 clusters were plotted according to UMAP algorithms. (D) The proportion of each cluster across samples. (E) Using SpatialX Software, the significantly upregulated and downregulated genes in each cluster were determined and subjected to GO enrichment analysis (Rectome). The top GO terms of each cluster are presented as bar graphs with normalized enrichment score (NES). (F) Region segmentation analysis (with a 100 μm radius) based on spatial gene correlation showing 5 distinct gene modules across samples. (G) Correlation of signature gene expression of APP, IFN-γ signaling, and type I IFN response between Louvain clusters and segmented gene modules. (H) Imaging segmentation analysis based on cellular compartment–specific hallmark features showing distinct tumor cores and reactive stroma compartments across H&E-stained samples. (I) The proportion of each spatial region identified in F across tumor cores and reactive stroma compartments.