AUTHOR=Chen Yu , Huang Yingying , Gao Xuan , Li Yi , Lin Jing , Chen Lizhu , Chang Lianpeng , Chen Gang , Guan Yanfang , Pan Leong Kin , Xia Xuefeng , Guo Zengqing , Pan Jianji , Xu Yaping , Yi Xin , Chen Chuanben 

TITLE=CCND1 Amplification Contributes to Immunosuppression and Is Associated With a Poor Prognosis to Immune Checkpoint Inhibitors in Solid Tumors

JOURNAL=Frontiers in Immunology

VOLUME=11

YEAR=2020

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2020.01620

DOI=10.3389/fimmu.2020.01620

ISSN=1664-3224

ABSTRACT=<p><italic>Cyclin D1 (CCND1)</italic> amplification relevant to malignant biological behavior exists in solid tumors. The prevalence and utility of <italic>CCND1</italic> amplification as a biomarker for the clinical response to treatment with immune checkpoint inhibitors (ICIs) are unknown. Our study is a preliminary investigation mainly focused on the predictive function of <italic>CCND1</italic> amplification in the tumor microenvironment (TME) in the aspect of genome and transcriptome. We examined the prevalence of <italic>CCND1</italic> amplification and its potential as a biomarker for the efficacy of ICI therapy for solid tumors using a local database (<italic>n</italic> = 6,536), The Cancer Genome Atlas (TCGA) database (<italic>n</italic> = 10,606), and the Memorial Sloan Kettering Cancer Center (MSKCC) database (<italic>n</italic> = 10,109). Comprehensive profiling was performed to determine the prevalence of <italic>CCND1</italic> amplification and the correlation with the prognosis and the response to ICIs. A <italic>CCND1</italic> amplification occurs in many cancer types and correlates with shorter overall survival and inferior outcomes with ICI therapy. Transcriptomic analysis showed various degrees of immune cell exclusion, including cytotoxic cells, T cells, CD8<sup>+</sup> T cells, dendritic cells (DCs), and B cells in the TME in a TCGA <italic>CCND1</italic> amplification population. The gene set enrichment analysis suggested that <italic>CCND1</italic> amplification correlates with multiple aggressive, immunosuppressive hallmarks including epithelial–mesenchymal transition, transforming growth factor (TGF)-β signaling, KRAS signaling, phosphoinositide 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) signaling, p53 pathway, and hypoxia signaling in solid tumors. These findings indicate that <italic>CCND1</italic> amplification may be a key point related to immunosuppression in TME and multiple malignancy hallmarks, and it hinders not only the natural host immune responses but also the efficacy of ICIs.</p>