Abstract P4-05-24: A stroma-adjusted ZEB1 expression signature is associated with decreased immune cell infiltration and poor overall survival in breast cancer

Abstract

Abstract The epithelial-to-mesenchymal transition (EMT) is a critical physiologic process which can be activated by cancer cells to enhance metastatic and chemoresistant properties in experimental models. Recent studies have identified positive associations between the expression of EMT-associated gene signatures with both the immune response and survival in multiple cancer types. Although these studies relied upon whole-tumor RNA sequencing data, which can be confounded by infiltrating immune and stromal cells, they failed to investigate this potential confounding effect. In this study, we comprehensively dissected the associations between the expression of multiple EMT transcription factors with stromal and immune cell tumor infiltration in breast cancer. We demonstrated that previously-reported associations between the expression of EMT marker genes and immune activity were confounded by stromal cell infiltration. Adjusting for this confounding effect eliminated these reported associations. Interestingly, we discovered that stroma-adjusted ZEB1 expression has a unique, inverse association with immune cell activity in multiple cancer types, most significantly in breast cancer. Further analysis revealed that ZEB1 is significantly correlated with reduced tumor infiltration of multiple immune cell types. By deriving a high-confidence stroma-adjusted ZEB1-activated gene signature, we confirmed that ZEB1 transcriptional activity has similar associations with both tumor immune activity and stromal content as ZEB1, thus identifying potential mechanisms underlying decreased immune cell infiltration. Finally, multivariate survival analysis reveals that the ZEB1 gene signature has significant associations with reduced overall survival in breast cancer patients. In conclusion, this study identifies a novel association between stroma-adjusted ZEB1 expression and tumor immune activity and addresses the critical issue of confounding between EMT-associated genes and tumor stromal content. Citation Format: C James Block, Guojun Wu. A stroma-adjusted ZEB1 expression signature is associated with decreased immune cell infiltration and poor overall survival in breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P4-05-24.