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Yuanliang Yan, Qiuju Liang, Yuanhong Liu, Shangjun Zhou, and Zhijie Xu

Immunotherapy has shown promising efficacy for breast cancer (BC) patients. Yet the predictive biomarkers for immunotherapy response remains lacking. Based on two GEO datasets, 53 differentially expressed genes (DEGs) associated with durvalumab treatment response, were identified. Using lasso and univariate Cox regression, 4 genes (COL12A1, TNN, SCUBE2 and FDCSP) revealed prognostic value in TCGA BC cohort. COL12A1 outperformed the others, without an overlap in its survival curve. Survival analysis by Kaplan-Meier plotter demonstrated that COL12A1 was negatively associated with BC patients’ prognosis. A COL12A1-based nomogram was further developed to predict the overall survival (OS) in BC patients. The calibration plot revealed an optimal agreement between nomogram-prediction and actual observation. Moreover, COL12A1 expression was significantly up-regulated in BC tissues and COL12A1 knockdown impaired the proliferation of MDA-MB-231 and BT549 cells. GO, KEGG and GSEA pathway analyses indicated that the function of COL12A1 was related to immunity-related pathways. Immunological analyses illustrated that COL12A1 was correlated with M2 macrophage infiltration and M2 macrophage markers (TGF-β1, IL-10, CSF1R and CD163) in BC. Immunohistochemistry staining further revealed a highly positive relationship of COL12A1 with TGF-β1. The co-incubated models of BC cells and M2 macrophges showed COL12A1 knockdown suppressed M2 macrophage infiltration. Additionally, silencing COL12A1 suppressed TGF-β1 protein expression, and treating with TGF-β1 could reverse the inhibitory effects on M2 macrophage infiltration by COL12A1 knockdown. Using immunotherapy datasets, we also found elevated expression of COL12A1 predicted poor response to anti-PD-1/PD-L1 therapy. These results reinforce current understanding of COL12A1’ roles in tumorigenesis and immunotherapy response in BC.