標靶鈣黏附蛋白-11增強膀胱癌細胞焦亡所調控之抗癌免疫反應

黃一勝^1,3,4、蔡德甫¹、仇光宇¹、何肇晏¹、張安辰²

¹新光醫院 泌尿科，²轉譯醫學中心；³台北醫學大學 醫學院；⁴輔仁大學 醫學院

Cadherin-11 blockade activates pyroptosis-mediated anti-tumor immunity in bladder cancer

Thomas I-Sheng Hwang^1,3,4, Te-Fu Tsai ¹, Kuang-Yu Chou¹, Chao-Yen Ho¹, and An-Chen Chang²

Department of Urology¹ and Translational Medicine Center², 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:

Bladder cancer (BC) is the fifth most diagnosed tumor and the second leading cause of death in patients with genitourinary tract malignancies. Pyroptosis represents a form of cell death that is triggered by proinflammatory signals and associated with inflammation. Cadherin-11 (CDH-11), a type II cadherin, mediates cell-cell and cell-extracellular matrix adhesion. Recently, the role of CDH-11 in promoting cancer progression has attracted increased attention. Here, we aim to explore whether targeting CDH-11 reduces BC cell invasiveness and induces pyroptosis-mediated anti-tumor immunity.

Materials and Methods:

Transwell assay was performed to detect cell migration and invasion ability. The levels of CDH-11 protein expression in human BC tissue were detected by immunohistochemistry staining. Lactate dehydrogenase (LDH) assay and calcein AM staining-based cytotoxicity was performed to detect cell pyroptosis and natural killer (NK) cells mediated cytotoxicity, respectively. Human antibody array was used to measure the levels of inflammatory cytokines expression in BC. The subcutaneous tumor model was performed to study CDH-11-mediated tumor growth in vivo. 

Results:

We observed higher levels of CDH-11 expression in BC patients compared with healthy individuals, which was also positively correlated with clinical staging, lymphatic metastasis and poor overall survival. From in vitro analysis, CDH-11 blockade in BC cells significantly impeded cell invasiveness. Moreover, CDH-11 blockade increased bubble-like protrusions on the cell surface and LDH release, indicating CDH-11 blockade could promote cell pryoptosis in BC. Mechanistically, CDH-11 blockade triggered PD-L1-mediated GSDM-D expression, which in turn GSDMD N-terminal domain assembled membrane pores to induce cell pyroptosis. A more detailed analysis revealed that CDH-11-regulated cell pyroptosis could promote pro-inflamantory cytokine CCL3 releasing in the tumor microenvironment, and thus increased the cytotoxic action of NK cells to BC. Finally, CDH-11 blockade suppressed tumor growth in in vivo analysis.

Conclusions: 

These findings identify a novel function of CDH-11 by showing that targeting CDH-11 inhibits cell invasion and promotes pyroptosis-mediated antitumor immunity through CCL3 in BC. Targeting CDH-11 may be a worthwhile therapeutic strategy in the management of BC.