PDF(Pubmed)
Abstract：
Resistance to HER2-targeted therapy is the major cause of treatment failure in patients with HER2+ breast cancer (BC). Given the key role of immune microenvironment in tumor development, there is a lack of an ideal prognostic model that fully accounts for immune infiltration. In this study, WGCNA analysis was performed to discover the relationship between immune-related signaling and prognosis of HER2+ BC. After Herceptin-resistant BC cell lines established, transcriptional profiles of resistant cell line and RNA-sequencing data from GSE76360 cohort were analyzed for candidate genes. 85 samples of HER2+ BC from TCGA database were analyzed by the Cox regression, XGBoost and Lasso algorithm to generalize a credible immune-related prognostic index (IRPI). Correlations between the IRPI signature and tumor microenvironment were further analyzed by multiple algorithms, including single-cell RNA sequencing data analysis. Patients with high IRPI had suppressive tumor immune microenvironment and worse prognosis. The suppression of type I interferon signaling indicated by the IRPI in Herceptin-resistant HER2+ BC was validated. And we elucidated that the suppression of cGAS-STING pathway is the key determinant underlying immune escape in Herceptin-resistant BC with high IRPI. A combination of STING agonist and DS-8201 could serve as a new strategy for Herceptin-resistant HER2+ BC.
摘要：
对HER2靶向治疗的抗性是HER2+乳腺癌(BC)患者治疗失败的主要原因。鉴于免疫微环境在肿瘤发展中的关键作用，缺乏一个理想的预后模型来完全解释免疫浸润.在这项研究中,进行WGCNA分析以发现免疫相关信号与HER2BC预后之间的关系。赫赛汀抗性BC细胞系建立后，对GSE76360队列的耐药细胞系转录谱和RNA测序数据进行了候选基因分析.通过Cox回归分析来自TCGA数据库的85个HER2+BC样本，XGBoost和Lasso算法推广可靠的免疫相关预后指数(IRPI)。通过多种算法进一步分析了IRPI特征与肿瘤微环境之间的相关性。包括单细胞RNA测序数据分析。高IRPI患者肿瘤免疫微环境抑制，预后较差。证实了在赫赛汀抗性HER2+BC中由IRPI指示的I型干扰素信号传导的抑制。并且我们阐明了cGAS-STING途径的抑制是具有高IRPI的赫赛汀抗性BC中免疫逃逸的关键决定因素。STING激动剂和DS-8201的组合可以作为赫赛汀抗性HER2+BC的新策略。
