Elevated mrna level of y-box binding protein 1 indicates unfavorable prognosis correlated with macrophage infiltration and t cell exhaustion in luminal breast cancer

Abstract

Purpose: The Y-box binding protein 1 (YBX1) gene encodes the multifunctional protein YB1 that is associated with the dysregulation of numerous cancer-related genes. However, the prognostic value of YBX1 and its correlation with immune cell infiltration in breast cancer (BRCA) remain unclear. Methods: YBX1 expression data in various malignancies were obtained from Oncomine, Tumor Immune Estimation Resource (TIMER), Cancer Cell Line Encyclopedia, UALCAN and cBio Cancer Genomics Portal databases. Survival data were analyzed with Kaplan– Meier plotter. Immune cell infiltration and its association with YBX1 expression level were assessed with TIMER and LinkedOmics. YB1 expression was evaluated by immunohistochemistry and Western blotting, and changes in cancer cell viability and T cell activity following YBX1 knockdown were assessed with an immunocyte–tumor cell co-culture assay. Results: YBX1 was downregulated in the BRCA cohort, which was closely associated with worse prognosis in the luminal A subtype (overall survival [OS]: hazard ratio [HR] 1.93, 95% confidence interval [CI] 1.22–3.05, P = 0.0042; recurrence-free survival [RFS]: HR 1.85, 95% CI 1.51–2.28, P = 3.1e-9) and luminal B subtype (OS: HR 1.08, 95% CI 0.68– 1.70, P = 0.75; RFS: HR 1.29, 95% CI 1.02–1.62, P = 0.03). YBX1 expression was positively correlated with the M2 macrophage infiltration and expression of T cell exhaustion markers such as indoleamine 2,3-dioxygenase 1 (IDO1) (rs = 0.388, P = 4.93e-37) and cytotoxic T-lymphocyte-associated protein 4 (CTLA4) (rs = 0.321, P = 2.54e-25) in luminal BRCA. Kaplan–Meier analysis revealed a correlation between YBX1 expression, M2 infiltration and survival outcome. Co-culture with macrophages or T cells enhanced the decrease in luminal BRCA cell viability induced by YBX1 knockdown. Conclusion: High YBX1 mRNA levels predict a poor prognosis in luminal BRCA, which is correlated with M2 macrophage infiltration and T cell exhaustion in the tumor microenvironment. Combining classic therapeutics with immune checkpoint inhibitors and M1 polarization agents may be an effective treatment strategy for luminal BRCA with YBX1 overexpression.