Cadherin-11透過PD-L1調控膀胱癌細胞焦亡與誘發抑癌免疫反應

黃一勝1,2,3,4、張安辰2、蔡德甫1、仇光宇1、何肇晏1、陳宏恩1

1新光醫院 泌尿科，2中央研究室；3台北醫學大學 醫學院；4輔仁大學 醫學院

Cadherin-11 regulates cell pyroptosis and induces anti-tumor immunity through PD-L1 in bladder cancer

Thomas I-Sheng Hwang1,3,4, An-Chen Chang2, Te-Fu Tsai1, Kuang-Yu Chou1, Chao-Yen Ho1 and Hung-En Chen1

Department of Urology1 and Central Laboratory2, Shin Kong Wu Ho-Su Memorial Hospital; Department of Urology, Taipei Medical University3; Division of Urology, School of Medicine, Fu-Jen Catholic University4, Taipei, Taiwan.

Purpose:

Pyroptosis, a new type of programmed cell death regulated by nuclear PD-L1, has received widespread attention recently. We aim to explore whether co-targeting cadherin-11 (CDH-11) with chemotherapy induce the pyroptosis of bladder cancer (BC), which in turn may activate anti-tumor immunity to cure cancer.

Materials and Methods:

The BC cell line UMUC-3 was cultured in -MEM medium and transfected with control or CDH-11 shRNA (1 g/uL) by using ViaFect transfection reagent. Western blot and quantitative real-time PCR (qPCR) were used to measure the levels of indicated protein and mRNA expression, respectively. Human bladder cancer tissue array was used to detect CDH-11 expression by immunohistochemistry staining. The assay of lactate dehydrogenase (LDH) was performed to detect cell pyroptosis.

Results:

We found that treatment of BC cells with CDH-11 shRNA induced nuclear PD-L1 protein expression. Moreover, CDH-11 shRNA treatment elevated chemosensitivity of BC cells to cisplatin by inducing cell death. We next questioned whether the death pattern of cells treated with CDH-11 shRNA plus cisplatin switches from apoptosis to pyroptosis. Large bubbles (typical morphological feature of pyroptosis) and significantly increased LDH release were indeed observed under CDH-11 shRNA and cisplatin co-treatment. A more detailed analysis revealed that CDH-11 shRNA induces PD-L1 protein expression via the MAPK signaling pathway. Finally, we observed higher levels of CDH-11 expression in patients with BC, which was also correlated with poor overall survival. NK cytotoxicity system has been established in our lab. In the future, we will examine whether CDH-11 shRNA/cisplatin-induced pyroptosis activate the cytotoxic action of NK to BC cells.

Conclusions:

These findings identify a novel function of CDH-11 by showing that CDH-11 regulates BC pyroptosis via activating PD-L1 expression.