PARP inhibitors restore NK cell function via secretory crosstalk with tumor cells in prostate cancer
Zheng Chao, Le Li, Xiaodong Hao, Hao Peng, Yanan Wang, Chunyu Zhang, Xiangdong Guo, Peikun Liu, Sheng Ma, Junbiao Zhang, Guanyu Qu, Yuzheng Peng, Zhengping Wei, Jing Luo, Bo Liu, Peixiang Lan, Zhihua Wang
Zheng Chao, Le Li, Xiaodong Hao, Hao Peng, Yanan Wang, Chunyu Zhang, Xiangdong Guo, Peikun Liu, Sheng Ma, Junbiao Zhang, Guanyu Qu, Yuzheng Peng, Zhengping Wei, Jing Luo, Bo Liu, Peixiang Lan, Zhihua Wang
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Research Article Immunology Oncology

PARP inhibitors restore NK cell function via secretory crosstalk with tumor cells in prostate cancer

Abstract

Prostate cancer (PCa) is one of the most frequently diagnosed malignancies and the main cause of cancer-related death in men worldwide. Poly(ADP-ribose) polymerase inhibitors (PARPi) have been approved for the treatment of PCa harboring BRCA1/2 mutations. While the survival benefits conferred by PARPi may extend beyond this specific patient population based on evidence from recent clinical trials, the underlying mechanisms remain unexplored. Here, we demonstrate that PARPi substantially restored NK cell functions by promoting cyclophilin A (CypA) secretion from PCa cells, which correlated with improved prognosis in PCa patients from our and public cohorts. Mechanistically, tumor-derived CypA specifically from PCa cells bound to ANXA6 and activated the downstream FPR1 signaling pathway, leading to increased mitochondrial oxidative phosphorylation and NK cell activation. Pharmacological inhibition of CypA blocked FPR1/AKT signaling and diminished the cytotoxic effects of NK cells, thereby compromising the therapeutic efficacy of PARPi against PCa. Conversely, combining NK cell adoptive transfer therapy with PARPi markedly prolonged survival in mice bearing PCa. Collectively, we reveal a unique secretory crosstalk between PCa cells and NK cells induced by PARPi and propose a promising strategy for treating PCa.

Authors

Zheng Chao, Le Li, Xiaodong Hao, Hao Peng, Yanan Wang, Chunyu Zhang, Xiangdong Guo, Peikun Liu, Sheng Ma, Junbiao Zhang, Guanyu Qu, Yuzheng Peng, Zhengping Wei, Jing Luo, Bo Liu, Peixiang Lan, Zhihua Wang

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Figure 1

PARPi revitalize NK cells in the PCa microenvironment.

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PARPi revitalize NK cells in the PCa microenvironment. (A) Expression of...
(A) Expression of CD16, CD56, NCR1, and KLRF1 in PCa versus normal tissues (TCGA). The box-and-whisker plots depict the minimum and maximum values (whiskers), the upper and lower quartiles, and the median. (B) Immunohistochemical staining of NCR1 in high- and low-grade PCa tissues collected at Tongji Hospital. Scale bars: 100 μm. (C) Proportion of NCR1 expression in patients with high-grade (N = 10) versus intermediate/low-grade (N = 10) PCa. (D) Treatment regimens for C57BL/6 mice bearing CRPC-PPSM starting on day 8 after inoculation: enzalutamide (10 mg/kg, oral, daily), anti–PD-1 (200 μg/kg, i.p., every 3 days), docetaxel (10 mg/kg, i.v., weekly), and mefuparib (40 mg/kg, oral, every 2 days). Mice were euthanized on day 25 after tumor inoculation. (E) Tumor growth curves and tumor weights in mice from D for each treatment; N = 5 per group. Scale bars: 1 cm. (F) Immunofluorescence of tumors from D showing DAPI (blue), NK1.1 (red), GZMB (yellow), and PanCK (white). Scale bars: 20 μm. (G) Tumor growth curves and weights of C57BL/6 mice inoculated with RM-1 cells and treated with or without PARPi; N = 6 per group. Scale bars: 1 cm. (H) Tumor growth curves and weights of Rag1–/– γc–/– mice inoculated with RM-1 or RM-1 BRCA1-KO cells and treated with or without PARPi; N = 5 per group. Scale bars: 1 cm.(I–L) Flow cytometry analysis of NK cell proportions in tumors (I) and peripheral blood (K), GZMB+ proportion in TINKs (J), and TNF-α+ IFN-γ+ proportions in PBNKs (L) of mice from G; N = 5 per group. Tumor growth curve data are presented as mean ± SD and were analyzed by 2-way ANOVA with Tukey’s multiple-comparison test. Other data are presented as mean ± SEM. Data were analyzed by 1-way ANOVA (E and H) and Welch’s t test (G and I–L).