A High Immune-Related Index with the Suppression of cGAS-STING Pathway is a Key Determinant to Herceptin Resistance in HER2+ Breast Cancer
Ruizhao Cai, Qingshan Chen, Dechang Zhao, Yan Wang, Ling Zhou, Kaiming Zhang, Jialu Shan, Zhiling Li, Yuhong Chen, Hailiang Zhang, Gong‐Kan Feng, Xiao‐Feng Zhu, Rong Deng, Jun Tang
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.