Department of Breast Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China.
State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China.
Int J Biol Sci. 2024 Jun 17;20(9):3497-3514. doi: 10.7150/ijbs.94868. eCollection 2024.
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.
曲妥珠单抗耐药是 HER2 阳性乳腺癌（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，目前缺乏一个充分考虑免疫浸润的理想预后模型。本研究通过 WGCNA 分析发现了免疫相关信号与 HER2+BC 预后之间的关系。在建立曲妥珠单抗耐药 BC 细胞系后，分析了耐药细胞系的转录谱和 GSE76360 队列的 RNA-seq 数据，以寻找候选基因。对 TCGA 数据库中 85 例 HER2+BC 进行 Cox 回归、XGBoost 和 Lasso 算法分析，以概括一个可信的免疫相关预后指数（IRPI）。通过多种算法（包括单细胞 RNA 测序数据分析）进一步分析了 IRPI 特征与肿瘤微环境之间的相关性。IRPI 高表达的患者具有抑制性肿瘤免疫微环境和更差的预后。IRPI 提示曲妥珠单抗耐药 HER2+BC 中 I 型干扰素信号受到抑制，这得到了验证。我们阐明了 IRPI 高表达的曲妥珠单抗耐药 BC 中 cGAS-STING 通路的抑制是免疫逃逸的关键决定因素。STING 激动剂和 DS-8201 的联合应用可能为曲妥珠单抗耐药 HER2+BC 提供一种新的治疗策略。
