DLX2 Is a Potential Immune-Related Prognostic Indicator Associated with Remodeling of Tumor Microenvironment in Lung Squamous Cell Carcinoma: An Integrated Bioinformatical Analysis

Abstract

Background. It is still an unmet clinical need to identify potent biomarkers for immunotherapy on patients with lung squamous cell carcinoma (LUSC). Methods. In this study, we explored the differentially expressed genes (DEGs) that were simultaneously correlated with four pathways (i.e. CD8+αβT cell proliferation/differentiation/activation pathways and ferroptosis pathway) and possibly related to the remodeling of tumor microenvironment via the TCGA-LUSC dataset. Besides, four GEO datasets (GSE157009, GSE157010, GSE19188, and GSE126045) and IMvigor210 dataset were utilized for confirmation and validation. Results. The co-downregulated DEG DLX2 was selected for further analysis. Function enrichment analysis revealed that low-expression of DLX2 was closely related to various immune-related pathways like T/B/NK cell mediated immunity, interferon gamma/alpha response, and various autoimmune disease. DLX2-downregulated group was enriched in more immune-activating cells and lower tumor immune dysfunction and exclusion (TIDE) score. Via the Cancer Immunome Atlas (TCIA) database, lower expression of DLX2 was also found to be associated with better IPS score of PD-1/PD-L1 blockade ( $p<0.001$ ) as well as CTLA-4 combined with PD-1/PD-L1 blockade ( $p<0.001$ ). Furthermore, patients in DLX2-low group were found to have significant longer median OS than those in DLX2-high group in IMvigor210 dataset (10.8 vs 7.4 months; hazard ratio [HR]=0.74, 95% confidence interval [95%CI] 0.57-0.96; $p=0.024$ ). Conclusions. Our study on an integrated bioinformatical analysis implied that DLX2 could be served as a promising indicator for remodeling tumor microenvironment status and predicting ICI response of patients with LUSC.