CD73 inhibition overcomes adaptive immune resistance to PARP inhibiton 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
View: Text | PDF
Research In-Press Preview Immunology Oncology

CD73 inhibition overcomes adaptive immune resistance to PARP inhibiton 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 inhibitors (PARP inhibitor) are approved for mCRPC patients with homologous recombination repair (HRR) deficiencies, clinical trials combining Olaparib with PD-1/PD-L1 inhibitors have shown limited efficacy in unselected populations. To investigate the immunomodulatory effects of PARP inhibitor in an unbiased manner, we performed bulk RNA sequencing on HRR-proficient MycCaP cells treated with the PARP inhibitor (Olaparib) versus vehicle control. Transcriptomics 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 both human and mouse prostate cancer cell lines, with more pronounced effects in HRR-compromised PTEN knockout (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 interferon (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

×
Problems with a PDF?

This file is in Adobe Acrobat (PDF) format. If you have not installed and configured the Adobe Acrobat Reader on your system.

Having trouble reading a PDF?

PDFs are designed to be printed out and read, but if you prefer to read them online, you may find it easier if you increase the view size to 125%.

Having trouble saving a PDF?

Many versions of the free Acrobat Reader do not allow Save. You must instead save the PDF from the JCI Online page you downloaded it from. PC users: Right-click on the Download link and choose the option that says something like "Save Link As...". Mac users should hold the mouse button down on the link to get these same options.

Having trouble printing a PDF?

  1. Try printing one page at a time or to a newer printer.
  2. Try saving the file to disk before printing rather than opening it "on the fly." This requires that you configure your browser to "Save" rather than "Launch Application" for the file type "application/pdf", and can usually be done in the "Helper Applications" options.
  3. Make sure you are using the latest version of Adobe's Acrobat Reader.

Unedited blot and gel images - Download (172.96 KB)

Advertisement