Qiong Wu1, Lei Wang2, Huagen Wei3, Ben Li4, Jiaming Yang3, Zilin Wang3, Jianfeng Xu5, You Lang Zhou6, Bo Zhang7. 1. Medical School of Nantong University, Nantong 226001, Jiangsu Province, PR China; Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Nantong 226001, Jiangsu Province, PR China. 2. School of Life Sciences & Biotechnology, Shanghai Jiao Tong University, Shanghai 200025, PR China. 3. Medical School of Nantong University, Nantong 226001, Jiangsu Province, PR China. 4. Department of Cardiothoracic Surgery, Affiliated Hospital of Nantong University, Nantong 226001, Jiangsu Province, PR China. 5. Department of Imaging, Affiliated Hospital of Nantong University, Nantong 226001, Jiangsu Province, PR China. Electronic address: xujianfengct@sina.com. 6. Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Nantong 226001, Jiangsu Province, PR China. Electronic address: zhouyoulang@ntu.edu.cn. 7. Medical School of Nantong University, Nantong 226001, Jiangsu Province, PR China; Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Nantong 226001, Jiangsu Province, PR China. Electronic address: 1617011174@yxy.ntu.edu.cn.
Abstract
BACKGROUND: Although multiple key molecules in lung adenocarcinoma (LUAD) have been identified in recent years, the overall tumor microenvironment (TME) immune cell infiltration characterizations mediated by multiple key molecules remain little known. This study aimed to integrate the roles of multiple key molecules to evaluate patient prognosis and TME cell infiltration characterization as well as responses to immunotherapy. METHODS: Using combined LUAD cancer cohorts with 228 normal samples and 913 tumor samples, we comprehensively dissected the differences of genomic and TME cell infiltration landscapes between normal lung tissues and tumor tissues. The single-sample gene-set enrichment analysis (ssGSEA) was used to quantify the relative abundance of 24 cell infiltration. The riskScore signature was constructed using a least absolute shrinkage and selection operator (LASSO) Cox regression mode. RESULTS: Seven novel key molecules with significantly up-regulated expression in LUAD were determined. Survival analyses revealed their important prognostic values. LUAD microenvironment presented a markedly decreased infiltration of immune cells compared to normal lung tissues. We found tumors with up-regulated expression of these key molecules exhibited a significantly decreased TME cell infiltration and increased immune checkpoint molecule expression. The high riskScore subtype was characterized by decreased innate and adaptive immune cell infiltration. Activation of p53 signaling pathway and regulator T cells were observed in the high riskScore subtype, which were regarded as T-cell suppressive and could be responsible for poorer prognosis in this subtype (HR 1.83(1.27-2.63)). Multivariate analyses demonstrated the riskScore was a robust and independent prognostic biomarker, and its value in predicting immunotherapeutic outcomes was also confirmed (HR 1.70(1.22-2.37)). CONCLUSIONS: This study reveal a novel gene signature significantly related to patient prognosis and TME cell infiltration in LUAD. We demonstrated the integrated roles of multiple key molecules played a crucial role in shaping TME cell infiltration diversity and complexity. Evaluating the integrated characterization of multiple key molecules could contribute to predicting patients' response to immunotherapy and guiding more effective immunotherapy strategies.
BACKGROUND: Although multiple key molecules in lung adenocarcinoma (LUAD) have been identified in recent years, the overall tumor microenvironment (TME) immune cell infiltration characterizations mediated by multiple key molecules remain little known. This study aimed to integrate the roles of multiple key molecules to evaluate patient prognosis and TME cell infiltration characterization as well as responses to immunotherapy. METHODS: Using combined LUAD cancer cohorts with 228 normal samples and 913 tumor samples, we comprehensively dissected the differences of genomic and TME cell infiltration landscapes between normal lung tissues and tumor tissues. The single-sample gene-set enrichment analysis (ssGSEA) was used to quantify the relative abundance of 24 cell infiltration. The riskScore signature was constructed using a least absolute shrinkage and selection operator (LASSO) Cox regression mode. RESULTS: Seven novel key molecules with significantly up-regulated expression in LUAD were determined. Survival analyses revealed their important prognostic values. LUAD microenvironment presented a markedly decreased infiltration of immune cells compared to normal lung tissues. We found tumors with up-regulated expression of these key molecules exhibited a significantly decreased TME cell infiltration and increased immune checkpoint molecule expression. The high riskScore subtype was characterized by decreased innate and adaptive immune cell infiltration. Activation of p53 signaling pathway and regulator T cells were observed in the high riskScore subtype, which were regarded as T-cell suppressive and could be responsible for poorer prognosis in this subtype (HR 1.83(1.27-2.63)). Multivariate analyses demonstrated the riskScore was a robust and independent prognostic biomarker, and its value in predicting immunotherapeutic outcomes was also confirmed (HR 1.70(1.22-2.37)). CONCLUSIONS: This study reveal a novel gene signature significantly related to patient prognosis and TME cell infiltration in LUAD. We demonstrated the integrated roles of multiple key molecules played a crucial role in shaping TME cell infiltration diversity and complexity. Evaluating the integrated characterization of multiple key molecules could contribute to predicting patients' response to immunotherapy and guiding more effective immunotherapy strategies.
Authors: Zhou Jiawei; Mu Min; Xing Yingru; Zhang Xin; Li Danting; Liu Yafeng; Xie Jun; Hu Wangfa; Zhang Lijun; Wu Jing; Hu Dong Journal: Front Mol Biosci Date: 2020-10-27