佩你安在引發膀胱癌自然殺手細胞介導的免疫反應之作用

沈正煌¹、陳丕哲¹、蔡長佑¹、陳永恩²、希馬尼·庫馬里²

1嘉義基督教醫院泌尿外科; 2國立中正大學分子生物研究所

The Effects of Cyproheptadine in Eliciting Natural Killer cell-mediated Immune Response in Bladder Cancer

Cheng-Huang Shen¹, Pi-Che Chen¹_, Chang-Yu, Tsai¹,Michael W. Y. Chan ²_, Himani Kumari²

1Department of Urology, Chiayi Christian Hospital, Chiayi, Taiwan; 2National Chung Cheng University, Chiayi, Taiwan;

Purpose: Bladder cancer is one of the most common occurring cancers in urothelial carcinoma. Previous study suggested that cancer cells undergo immunoevasion due to epigenetic silencing of NKG2DL, in which NKG2D-NKG2DL interaction induced natural killer (NK) cell-mediated cytotoxicity. We hypothesized that NK-mediated cytotoxicity can be reactivated by restoring expression of NKG2DL on tumor cells.

Materials and Methods: The effect of cyproheptadine (CPH) on gene expression in bladder cancer cell lines were examined by RNA-Seq and RT-PCR. Co-culture experiment was performed to examine the cytotoxicity of NK-92 cell to bladder cancer cells. ChIP-PCR was used to examine the histone modifications at ULBP2 promoter. Syngeneic mice model was used to examine the effect of CPH and immune checkpoint blockade on the growth MB49 bladder cancer cells.

Results: Results from RNA-seq showed an upregulation of ULBP2, a NKG2DL, in bladder cancer cells treated with CPH. Upregulation of ULBP2, in accompanied with the enrichment of H3K27Ac and H3K4me3 at ULBP2 promoter, was observed in cells treated with CPH. Increased NK-specific lysis was observed in CPH-treated bladder cancer cells co-cultured with NK-92 cells. Treatment of CPH enhanced the efficacy of immune checkpoint inhibitor in a syngeneic mice bladder cancer model.

Conclusion: Our results suggested that CPH may be a novel HDAC inhibitor which may elicit anti-tumor immune response in NK-cell dependent manner.