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 4

PARPi plus CD73 blockade substantially reduces tumor growth via CD8+ T cell–dependent mechanisms.

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PARPi plus CD73 blockade substantially reduces tumor growth via CD8+ T c...
(A) Syngeneic prostate cancer models (MycCaP, MycCaP-PTEN–KO, and DKO) were treated with vehicle, olaparib, α-CD73, or the combination (n = 5–10). Tumor growth kinetics (top) and survival curves (bottom) were recorded across treatment groups. (B) Tumor-infiltrating immune cells from each treatment group were analyzed by CyTEK and visualized using an unbiased UMAP analysis. (C) CyTEK analysis of the frequencies of CD3+, CD4+, and CD8+ T lymphocytes across treatment groups (n = 5). (D) Characterization of the Tpex subset and exhausted-like hallmark TOX expression in intratumoral CD8+ T cells (n = 5). (E) Expression of CD40 on tumor-infiltrating DCs across treatment groups (n = 5). (F) PD-L1 expression on PMN-MDSCs across treatment groups (n = 5). (G) Growth curves and tumor weights of MycCaP-NT and MycCaP-CD73–KD tumors treated with vehicle or olaparib (n = 9–10). (H–J) Representative immunofluorescence staining of CD8 and granzyme B (GZB) in MycCaP tumor sections (H), with quantification of CD8+ T cell density (I) and GZB+ CD8+ T cell density (J) across NT, olaparib, CD73-KD, and olaparib-treated control versus CD73-KD tumors (n = 5). White arrow, CD8+ GZB– cells; white arrowhead, CD8+ GZB+ cells. Scale bar: 100 μm. (K) Tumor growth in mice treated with combined olaparib and α-CD73 following CD8+ cell depletion (n = 7–8). Results in A are representative of 3 independent experiments. Data were analyzed by 2-way ANOVA (A, C–G, and I–K) or log-rank test for survival curves (A). Data plotted are mean ± SEM from biological replicates. *P < 0.05, **P < 0.01, ***P < 0.001.