CXCL9 Is a Potential Biomarker of Immune Infiltration Associated With Favorable Prognosis in ER-Negative Breast Cancer

Abstract

The chemokine CXCL9 (C-X-C motif chemokine ligand 9) has been reported to be required for antitumour immune responses following immune checkpoint blockade. In this study, we sought to investigate the potential value of CXCL9 according to immune responses in patients with breast cancer (BC). A variety of open-source databases and online tools were used to explore the expression features and prognostic significance of CXCL9 in BC and its correlation with immune-related biomarkers followed by subsequent verification with immunohistochemistry experiments. The CXCL9 mRNA level was found to be significantly higher in BC than in normal tissue and was associated with better survival outcomes in patients with ER-negative tumours. Moreover, CXCL9 is significantly correlated with immune cell infiltration and immune-related biomarkers, including CTLA4, GZMB, LAG3, PDCD1 and HAVCR2. Finally, we performed immunohistochemistry with breast cancer tissue samples and observed that CXCL9 is highly expressed in the ER-negative subgroup and positively correlated with the immune-related factors LAG3, PD1, PDL1 and CTLA4 to varying degrees. These findings suggest that CXCL9 is an underlying biomarker for predicting the status of immune infiltration in ER-negative breast cancer.

A comprehensive bioinformatics analysis to identify potential prognostic biomarkers among CC and CXC chemokines in breast cancer

“…Elevated CXCL9 level has been proved to be a good prognostic biomarker for the TNBC subgroup, while in the luminal A subgroup of patients, CXCL9 overexpression was correlated with poor prognostic characteristics 62 . Moreover, high CXCL9 expression has been related to improved survival in ER-negative BC 63 . We observed that higher CXCL9 expression appears to be associated with prolonged OS.…”

Analysis of Genomic Alterations Associated with Recurrence in Early Stage HER2-Positive Breast Cancer

“…A large-scale meta-analysis showed that clonal tumor mutation burden and CXCL9 expression were the strongest predictors of ICI responses across seven tumor types [ 42 ]. Liang et al reported that elevated levels of CXCL9 mRNA were associated with favorable outcomes in HR-negative breast cancer and CXCL9 was correlated with immune cell infiltration and immune-related biomarkers [ 43 ]. TIS score was developed as a predictive biomarker of ICIs from a large cohort of pembrolizumab-treated patients across nine different tumor types and the predictive utility of TIS score has been verified in many other studies [ 15 , 44 , 45 , 46 ].…”

Biomarkers of response to PD-1 pathway blockade

“…One study identified an abundance of myeloid cells expressing CXCL9, a cytokine induced by IFN-γ, in responders to atezolizumab and avelumab [ 46 ]. An analysis of clinical trial datasets for avelumab and atezolizumab showed a 2.4- and 2.8-fold increase in overall survival respectively for patients with the highest CXCL-9 expression compared to the lowest, which may be due to the CXCL9-CXCR3 axis promoting PD-L1 expression and increasing T cell recruitment [ 47 – 49 ]. This suggests a role for the analysis of other immune cells in the TME besides lymphocytes.…”