Increased PD-L1 Expression in Acquired Cisplatin-Resistant Lung Cancer Cells via Mir-181a.

Abstract

Cancer immunotherapy has dramatically improved the prognosis of non-small cell lung cancer (NSCLC). In tumor cells, programmed death ligand-1 (PD-L1), also known as cluster of differentiation 274 (CD274), is a key target for cancer immunotherapy. Cisplatin (CDDP), a first-class NSCLC treatment drug, reportedly induces PD-L1 expression, and regulates cancer immunity. Herein, the regulatory mechanism of PD-L1 was investigated in CDDP-treated NSCLC and acquired CDDP-resistant NSCLC. Two types of NSCLC cell lines, A549 and H69, and their CDDP-resistant cell lines, A549R and H68R, were used to investigate PD-L1 expression and microRNA mir-181a expression. Murine lung cancer LL/2 cells were injected to mice for in vivo study. Although CDDP induced PD-L1 expression in A549 and H69 cells, A549R and H69R cells expressed extremely higher levels of PD-L1. CDDP-induced mir-181a was detected in A549 and H69 cells, but not A549R and H69R cells. Moreover, the CDDP-induced ATM-mir-181a-c-FOS pathway repressed PD-L1 expression in A549 cells, while A549R cells blocked this negative regulatory mechanism to further increase PD-L1 expression. Exogenous mir-181a in LL/2 cells could repress the intratumoral exhausted T cells, and increase the T cells function, and repress the tumor growth. Increased PD-L1 expression in acquired cisplatin-resistant lung cancer cells is dependent on mir-181a in NSCLC.