A stroma-corrected ZEB1 transcriptional signature is inversely associated with antitumor immune activity in breast cancer

Abstract

The epithelial-to-mesenchymal transition (EMT) is an essential developmental process which can be hijacked by cancer cells, leading to enhanced metastasis and chemoresistance in experimental models. Recent studies have linked gene expression of EMT-associated gene signatures to increased inflammatory immune response in multiple cancer types. However, these studies did not account for the potential confounding effects of gene expression by tumor-infiltrating mesenchymal stromal cells. In this study, we comprehensively dissect the associations between multiple EMT transcription factors and EMT markers with stromal and immune tumor infiltration. We find that EMT-related genes are highly correlated with intratumoral stromal cell abundance and identify a specific relationship between stroma-corrected ZEB1 expression and decreased immune activity in multiple cancer types. We derive a stroma-corrected ZEB1-activated transcriptional signature and demonstrate that this signature includes several known inhibitors of inflammation, including BMPR2. Finally, multivariate survival analysis reveals that ZEB1 and its expression signature are significantly associated 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.

Analysis of genomics and immune infiltration patterns of epithelial-mesenchymal transition related to metastatic breast cancer to bone

“…Currently, a key issue regarding immunotherapy for BC patients is the limited understanding of the complexity of the tumors, tumor heterogeneity, and immune escape mechanisms. In addition, there is a lack of precise biomarkers to evaluate the efficacy of tumor immunotherapy, and the development of new immunotherapy targets and prognostic markers is necessary [29] . Wei et al.…”

“…We found that the abundances of resting NK cells, M0 macrophages, and M2 macrophages were substantially different between HRG and LRG. In addition, many international studies have shown that BMP2, BMPR2, GREM1, HGF, MCAM, TGFBR1, and other genes might promote distant metastasis and the local progression of BC [29] , [30] , [31] , [32] , [33] , [34] , [35] .…”

Noncoding RNAs: the shot callers in tumor immune escape

“…112 There is also evidence that these transcription factors are associated with immune escape. 113,116 miRNAs such as miR-21, miR-137, miR-34a, and miR-106a/b are known to regulate EMT by targeting these transcription factors (Table 4). In colorectal cancer, miR-21 can downregulate the expression of Snail and E-cadherin to inhibit EMT.…”

Zinc finger E‐box binding homeobox 1 and atherosclerosis: New insights and therapeutic potential

“…Numerous studies have shown that M1‐polarized macrophages are associated with inflammatory activity and promote the destabilization of atherosclerotic plaques, whereas M2‐polarized macrophages are responsible for inhibiting inflammatory responses and enhance atherosclerotic plaque stability (Colin et al, 2014; H. Li, Jiang, et al, 2018; Tabas & Bornfeldt, 2016). Recent studies have found that ZEB1 is negatively correlated with multiple immune cell types, including Th1 cells and M1 macrophages (Block et al, 2019; Smita et al, 2018). Moreover, overexpression of ZEB1 significantly decreases the levels of proinflammatory cytokines and chemokines, such as CCL2, CCL4, IL‐6, IL‐18, IL‐1α, IFN‐γ, TNF, NOS2/INOS, and MIF (Block et al, 2019; Siles et al, 2019).…”

“…Recent studies have found that ZEB1 is negatively correlated with multiple immune cell types, including Th1 cells and M1 macrophages (Block et al, 2019; Smita et al, 2018). Moreover, overexpression of ZEB1 significantly decreases the levels of proinflammatory cytokines and chemokines, such as CCL2, CCL4, IL‐6, IL‐18, IL‐1α, IFN‐γ, TNF, NOS2/INOS, and MIF (Block et al, 2019; Siles et al, 2019). These cytokines or chemokines have been implicated in macrophage polarization to M1 phenotype.…”