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 4

CypA enhances mitochondrial oxidative phosphorylation in NK cells.

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CypA enhances mitochondrial oxidative phosphorylation in NK cells. (A) A...
(A) Apoptosis levels of RM-1 cells (transfected with CypA plasmid or vehicle control) cocultured with mouse NK cells at ratios of 1:0, 1:5, and 1:10 for 24 hours, as assessed by annexin V/PI staining. (B) Experimental design of the tumor cell–NK cell coculture killing assay. Original magnification, ×100. (C) Coculture system of tdTomato-labeled (red) RM-1–vehicle control cells and BFP-labeled (blue) RM-1–CypA-OE cells at equal numbers. Apoptosis rates of fluorescently labeled tumor cells after 24 h NK cell–mediated killing, as determined by flow cytometry; N = 6 per group. BFP, blue fluorescent protein. (D and E) IFN-γ (D) and GZMB (E) levels in NK cells cocultured with RM-1 cells (as described in A); N = 5. (F) Purified mouse splenic NK cells (purity validated) cultured with recombinant CypA protein or isotype control. (G and H) Flow cytometry analysis of TNF-α and IFN-γ levels (G) and statistical quantification (H) in NK cells treated with recombinant CypA or isotype control; N = 5. (I) RNA-seq analysis of transcriptomic changes in NK cells exposed to CypA. (J) KEGG enrichment analysis showing upregulated oxidative phosphorylation in NK cells. (K–N) Cellular energy metabolism analysis: oxygen consumption rate (K and L) and extracellular acidification rate (M and N) in NK cells. (O and P) Mitochondrial membrane potential assay evaluating aerobic respiration capacity (O) and statistical results (P) in NK cells; N = 4. Data are presented as mean ± SEM and were analyzed by Welch’s t test.