Breast Cancer: Targets and Therapy (Apr 2022)
Cross-Platform in-silico Analyses Exploring Tumor Immune Microenvironment with Prognostic Value in Triple-Negative Breast Cancer
Abstract
Victor C Kok,1,2 Charles CN Wang,2,3 Szu-Han Liao,2 De-Lun Chen2 1Division of Medical Oncology, Kuang Tien General Hospital Cancer Center, Taichung, 43303, Taiwan; 2Department of Bioinformatics and Medical Engineering, Asia University, Taichung, 41354, Taiwan; 3Center for Artificial Intelligence and Precision Medicine Research, Asia University, Taichung, 41354, TaiwanCorrespondence: Victor C Kok; Charles CN Wang, Email [email protected]; [email protected]: Only a proportion of triple-negative breast cancer (TNBC) is immunotherapy-responsive. We hypothesized that the tumor microenvironment (TME) influences the outcomes of TNBC and investigated the relevant signaling pathways.Materials and Methods: Immune score (IS) and stromal score (SS) were calculated using the ESTIMATE and correlated with the overall survival (OS) in TNBC. RNA-seq data from 115 TNBC samples and 112 normal adjacent tissues were retrieved. Validations in the methylation levels in 10 TNBC and five non-TNBC cell lines were obtained. Cox model overall survival (OS) validated the derived transcription factor (TF) genes in cBioPortal breast cancer patients.Results: SS-low predicts a higher OS compared with SS-high patients (P = 0.0081 IS-high/SS-low patients had better OS (P = 0.045) than IS-low/SS-high patients. More macrophages were polarized to the M2 state in patients with IS-low/SS-high patients (P < 0.001). Moreover, CIBERSORTx showed more CD8+ cytotoxic T-cells in IS-high/SS-low patients (p = 0.0286) and more resting NK cells in the IS-low/SS-high TME (P = 0.0108). KEGG pathway analysis revealed that overexpressed genes were enriched in the IL-17 and cytokine-cytokine receptor interaction pathways. The lncRNA DRAIC, a tumor suppressor, was consistently deactivated in the 10 TNBC cell lines. On the cBioPortal platform, we validated that 13% of ER-negative, HER2-unamplified BC harbored IL17RA deep deletion and 25% harbored TRAF3IP2 amplification. On cBioPortal datasets, the nine altered TF genes derived from the X2K analysis showed significantly worse relapse-free survival in 2377 patients and OS in 4819 invasive BC patients than in the unaltered cohort.Conclusion: Of note, the results of this integrated in silico study can only be generalized to approximately 17% of patients with TNBC, in which infiltrating stromal cells and immune cells play a determinant prognostic role.Keywords: triple-negative breast cancer, immune cells, tumor microenvironment, IL-17 signaling pathway, immune evasion, in silico study
