Down-regulation of RCC1 sensitizes immunotherapy by up-regulating PD-L1 via p27 kip1 /CDK4 axis in non-small cell lung cancer

• Published in: Journal of cellular and molecular medicine 2021-04, Vol.25 (8), p.4136-4147
• Main Authors: Zeng, Xiaozhu, Zhong, Maoxi, Yang, Yumeng, Wang, Zhi, Zhu, Yuxi
• Format: Article
• Language: English
• Subjects: Adenocarcinoma; Apoptosis; Bioinformatics; Biotechnology; Cell cycle; Cell proliferation; Cyclin-dependent kinase 4; Cyclin-dependent kinase inhibitor p27; Cytoplasm; Flow cytometry; Gene expression; Growth rate; Immune checkpoint inhibitors; Immunotherapy; Kinases; Lung cancer; Medical prognosis; Metastases; Monoclonal antibodies; Non-small cell lung carcinoma; PD-L1 protein; Proteins; Reagents; Signal transduction; Small cell lung carcinoma; Tumors
• ISSN: 1582-1838; 1582-4934
• DOI: 10.1111/jcmm.16383

In recent years, although Immune Checkpoint Inhibitors (ICIs) significantly improves survival both in local advanced stage and advanced stage of non-small cell lung cancer (NSCLC), the objective response rate of ICI monotherapy is still only about 20%. Thus, to identify the mechanisms of ICI resistance is critical to increase the efficacy of ICI treatments. By bioinformatics analysis, we found that the expression of regulator of chromosome condensation 1 (RCC1) in lung adenocarcinoma was significantly higher than that in normal lung tissue in TCGA and Oncomine databases. The survival analysis showed that high expression RCC1 was associated with the poor prognosis of NSCLC. And the expression of RCC1 was inversely related to the number of immune cell infiltration. In vitro, knockdown of RCC1 not only significantly inhibited the proliferation of lung adenocarcinoma cells but also increased the expression levels of p27 and PD-L1, and decreased the expression level of CDK4 and p-Rb. In vivo, knockdown of RCC1 significantly slowed down the growth rate of tumour, and further reduced the volume and weight of tumour model after treated by PD-L1 monoclonal antibody. Therefore, RCC1 could up-regulate the expression level of PD-L1 by regulating p27 /CDK4 pathway and decrease the resistance to ICIs. And this study might provide a new way to increase the efficacy of PD-L1 monoclonal antibody by inhibiting RCC1.