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 7

The combination of PARPi with adoptive NK therapy inhibits CRPC growth and prolongs survival.

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The combination of PARPi with adoptive NK therapy inhibits CRPC growth a...
(A) Mice bearing RM-1 tumors were treated with mefuparib and adoptive transfer of 105 NK cells every 2 days from day 8. Mice were euthanized on day 18 for tumor collection. (B and C) Tumor growth curves (B) and weights (C) in mice treated with adoptive NK cell therapy, PARPi, or combination therapy; N = 6; scale bars: 1 cm. (D) Immunofluorescence of tumors from mice treated with adoptive NK cells, PARPi, or combination therapy, showing DAPI (blue), NK1.1 (red), GZMB (yellow), and PanCK (white). Scale bars: 50 μm. (E and F) Quantification of average NK1.1+ cells (E) and GZMB+ NK1.1+ cells (F) per high-power field. Data are based on average counts from 5 random fields per sample; N = 5. (G) Mice bearing orthotopic PPSM tumors received mefuparib and 105 NK cells every 2 days from day 8. Mice were euthanized on day 18 for analysis or retained for survival observation. (H) In vivo small animal imaging of orthotopic prostate tumor growth on day 18. (I) Survival curves of orthotopic PCa mouse models. (J) Western blot confirming hPSMA expression in DU145 cells. (K) Design of CAR-NK cells targeting human PSMA. SP, signal peptide; TM, transmembrane. (L) Representative flow cytometry analysis showing the transduction efficiency of CAR-NK cells. (M) Establishment of the DU145-hPSMA in situ PCa implantation model. Subsequently, tumor-bearing mice were treated with mefuparib and 105 CAR-NK cells every 2 days from day 8. Mice were euthanized on day 24 for tumor collection. (N) Tumor weight in DU145-hPSMA–bearing mice treated with PARPi and/or CAR-NK cells; N = 6. Tumor growth curve data are presented as mean ± SD and were analyzed by 2-way ANOVA with Tukey’s multiple-comparison test. Survival curves were analyzed by a log-rank (Mantel-Cox) test. Other data are presented as mean ± SEM and were analyzed by 1-way ANOVA.