Cross-Platform in-silico Analyses Exploring Tumor Immune Microenvironment with Prognostic Value in Triple-Negative Breast Cancer

Victor C Kok; Charles C N Wang; Szu-Han Liao; De-Lun Chen

doi:10.2147/BCTT.S359346

Cross-Platform in-silico Analyses Exploring Tumor Immune Microenvironment with Prognostic Value in Triple-Negative Breast Cancer

Breast Cancer (Dove Med Press). 2022 Apr 12:14:85-99. doi: 10.2147/BCTT.S359346. eCollection 2022.

Authors

Victor C Kok^{1

2}, Charles C N Wang^{2

3}, Szu-Han Liao², De-Lun Chen²

Affiliations

¹ Division of Medical Oncology, Kuang Tien General Hospital Cancer Center, Taichung, 43303, Taiwan.
² Department of Bioinformatics and Medical Engineering, Asia University, Taichung, 41354, Taiwan.
³ Center for Artificial Intelligence and Precision Medicine Research, Asia University, Taichung, 41354, Taiwan.

Abstract

Introduction: 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: IL-17 signaling pathway; immune cells; immune evasion; in silico study; triple-negative breast cancer; tumor microenvironment.

Grants and funding

This study was partly supported by a research fund from the Ministry of Science and Technology, Taiwan, with the grant number as MOST 109-2321-B-468-001. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.