Down-regulation of RCC1 sensitizes immunotherapy by up-regulating PD-L1 via p27kip1 /CDK4 axis in non-small cell lung cancer.

Abstract

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 p27kip1 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 p27kip1 /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.

• Authors: Xiaozhu Zeng, Maoxi Zhong, Yumeng Yang, Zhi Wang, Yuxi Zhu
• Journal: Journal of cellular and molecular medicine (J Cell Mol Med) Vol. 25 Issue 8 Pg. 4136-4147 (04 2021) ISSN: 1582-4934 [Electronic] England
• PMID: 33630417 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2021 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.

Chemical References

• B7-H1 Antigen
• Biomarkers, Tumor
• CD274 protein, human
• CDKN1B protein, human
• Cell Cycle Proteins
• Guanine Nucleotide Exchange Factors
• Nuclear Proteins
• RCC1 protein, human
• Cyclin-Dependent Kinase Inhibitor p27
• CDK4 protein, human
• Cyclin-Dependent Kinase 4

Topics

• Adenocarcinoma of Lung (drug therapy, immunology, metabolism, pathology)
• Adult
• Aged
• Animals
• Apoptosis
• B7-H1 Antigen (genetics, metabolism)
• Biomarkers, Tumor (genetics, metabolism)
• Carcinoma, Non-Small-Cell Lung (drug therapy, immunology, metabolism, pathology)
• Cell Cycle Proteins (antagonists & inhibitors, genetics, metabolism)
• Cell Movement
• Cell Proliferation
• Cyclin-Dependent Kinase 4 (genetics, metabolism)
• Cyclin-Dependent Kinase Inhibitor p27 (genetics, metabolism)
• Female
• Gene Expression Regulation, Neoplastic (drug effects)
• Guanine Nucleotide Exchange Factors (antagonists & inhibitors, genetics, metabolism)
• Humans
• Immunotherapy (methods)
• Lung Neoplasms (drug therapy, immunology, metabolism, pathology)
• Male
• Mice
• Mice, Inbred C57BL
• Middle Aged
• Nuclear Proteins (antagonists & inhibitors, genetics, metabolism)
• Prognosis
• Survival Rate
• Tumor Cells, Cultured
• Xenograft Model Antitumor Assays
• Young Adult