細胞自噬抑制劑透過膀胱癌表現PD-L1而降低抗腫瘤免疫反應

蔡德甫1、張安辰2、仇光宇1、陳宏恩1、何肇晏、黃一勝1,3,4

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

Autophagy inhibitor increased-PD-L1 expression suppress the effect of antitumor immunity in bladder cancer

Te-Fu Tsai 1, An-Chen Chang2, Kuang-Yu Chou1, Hung-En Chen 1, Chao-Yen Ho1 and Thomas I-Sheng Hwang1,3,4

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:

Autophagy process frequently presents to protect cancer cells escaping from anticancer treatments as chemotherapy or radiotherapy, facilitating for the developing of cancer drug resistant. Contributing several clinical trials recommend using autophagic pharmacologic inhibitors alone or combining with other anticancer treatments to augment the clinical efficacy of therapy. Our previous study identified that high basal level of autophagic activity was presented in bladder cancer (BC). However, autophagy inhibitors effect on PD-L1 and anti-tumor immunity in BC are undetermined. 

Materials and Methods:

The immortalized uroepithelial cells (SV-HUC-1) and human BC cells (5637 and T24) were obtained from the Bioresource Collection and Research Center (BCRC; Hsinchu, Taiwan). Western blot was used to detect LC3-II and PD-L1 protein expression after autophagy inhibitor (CQ or bafilomycin A1) treatment for 24 h. The qPCR assay was performed to measure PD-L1 mRNA level. The membrane-bound PD-L1 expression was detected by Flow cytometry. Calcein AM (1μM), a cell-permeant dye, was used to analyze natural killer (NK) cell-mediated cytotoxicity of BC cells.

Results:

Firstly, we discovered that the basal level of LC3-II has a negative correlation with PD-L1 in BC cells. Treatment of BC cells with autophagy inhibitor (CQ or bafilomycin A1) promoted PD-L1 mRNA and total protein expression, as well as membrane-bound PD-L1 expression. Moreover, further data revealed that autophagy inhibitor-induced PD-L1 level underwent ERK/JNK/c-Jun activation; however, no effect was seen on NFB and PARP signaling pathways. We also discovered miR-34a play a key miRNA involving in this mechanism by showing that miR-34a directly suppressed PD-L1 mRNA translation. Finally, autophagy inhibitor-induced PD-L1 reduced cytotoxicity activity of NK cells to BC.

Conclusions:

The present finding provides a novel biological function of autophagy inhibitor in PD-L1 expression and autophagy inhibitor interfere the effect of antitumor immunity in BC. Hence, combinative treatment of autophagy inhibitor with anti-PD-L1 antibody is recommended in BC.

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    TUA人資客服組
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    台灣泌尿科醫學會
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    2021-05-24 10:22:26
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    2021-05-24 17:19:58
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