基于生物信息数据库分析CD47对肺鳞癌免疫微环境及其免疫治疗的影响

Research on Effect of CD47 on Immune Microenvironment and Immunotherapy of Lung Squamous Cell Carcinoma Based on Bioinformatics Database

关键词:  肺鳞癌  CD47  免疫微环境  化疗敏感性

Key words:  lung squamous cell carcinoma  CD47  immune microenvironment  chemotherapy sensitivity

摘要:

目的 采用生物信息学方法分析基因CD47对肺鳞癌免疫微环境的影响并预测其免疫治疗响应。方法 从The Cancer Genome Atlas (TCGA)数据库下载基因CD47在肺鳞癌组织和正常组织中的测序数据并分析其表达差异。采用基因集富集分析研究CD47富集的免疫相关通路；通过肿瘤免疫数据库(Tumor Immune Estimation Resource，TIMER)和TISIDB数据库(http://cis.hku.hk/TISIDB/TISIDB)分析肺鳞癌患者中CD47基因表达情况与肿瘤微环境免疫细胞浸润的关系；同时也分析了CD47和其他免疫检查点基因PD-1、PD-L1、CTLA-4、IDO1的相关性；采用pRRophetic和TIDE算法，预测CD47基因表达与化疗药物敏感性以及免疫治疗的响应。结果 与正常组织相比，CD47在肺鳞癌组织中低表达；CD47富集了免疫相关通路如炎症反应、干扰素α反应、干扰素γ反应和JAK-STAT通路。2个数据库分析结果显示，在肺鳞癌组织中CD47表达水平与B细胞、CD8⁺T细胞、CD4⁺T细胞、巨噬细胞、中性粒细胞以及树突状细胞呈正相关性。同时CD47与其他的免疫检查点PD-1、PD-L1、CTLA-4、IDO1均呈一定的正相关性，化疗敏感性结果显示，在肺鳞癌组织中，对于舒尼替尼、达沙替尼、阿霉素、吉西他滨等化疗药物，高表达CD47组IC₅₀值低于低表达组。但对于免疫治疗，其响应率却低于低表达组。结论 CD47在肺鳞癌组织中低表达，能激活免疫相关通路，对免疫治疗响应率高，可作为肺鳞癌新型分子标志物。

Abstract:

OBJECTIVE To investigate the effect of gene CD47 on immune microenvironment of lung squamous cell carcinoma and predict its immune response. METHODS The differences in the expression of CD47 between lung squamous cell carcinoma tissues and normal tissues were compared through The Cancer Genome Atlas(TCGA) databases. CD47 involved immune-related pathways were analyzed by Gene Set Enrichment Analysis(GSEA). Tumor Immune Estimation Resource(TIMER) databases and TISIDB databases(http://cis.hku.hk/TISIDB/TISIDB) were employed to analyze the relationship between CD47 gene expression in lung squamous cell carcinoma and immune cells infiltration in the tumor microenvironment. And further explored the associations between CD47 and other immune-related molecules such as PD-1, PD-L1, CTLA-4, IDO-1. Using the pRRophetic and TIDE algorithms, this study predicted the correlation between the expression of CD47 gene and chemotherapy drug sensitivity as well as the response to immunotherapy. RESULTS Compared with normal tissues, CD47 was lower expressed in lung squamous cell carcinoma tissues. It was found that CD47 could activate immune-related pathways such as the inflammatory response, interferon alpha response, interferon gamma response and JAK-STAT pathway. In lung squamous cell carcinoma tissues, the expression level of CD47 was significantly positively correlated with the infiltration level of B-cells, CD8⁺T-cells, CD4⁺T-cells, macrophage, neutrophils and dendritic cells according to the two databases. At the same time, CD47 showed a positive correlation with other immune checkpoints such as PD-1, PD-L1, CTLA-4, IDO1. The result of chemotherapy sensitivity indicated that in lung squamous cell carcinoma tissues, IC₅₀ values of high expression CD47 group were lower than that for chemotherapy drugs such as sunitinib, dasatinib, doxorubicin and gemcitabine. However, the response rate to immunotherapy was lower in the low expression group for the immunotherapy. CONCLUSION CD47 is low expressed in lung squamous tissue, it can activate immune related pathways, and has a high response rate to immunotherapy. It can be used as a novel molecular marker for lung squamous cell carcinoma.