Abstract 1703P
Background
Lung adenocarcinoma (LUAD) is one of the deadliest cancers worldwide and its long-term survival is less than 10%. Thus, searching for effective biomarkers to predict prognosis and screen for immunotherapy candidates is urgently needed. The present study aimed to unveil the association of CA4 with immune inhibitory components and its prognostic significance.
Methods
Gene expression profiles were retrieved from The Cancer Genomic Atlas Lung Adenocarcinoma cohort (TCGA - LAUD) (n = 567). We used the TIMER 2.0 for immune inhibitory cell infiltrates analysis and the cBioPortal tool for tumor mutational burden (TMB). Subsequently, we studied the methylation status of the gene promotor using ULCAN web. The enrichment analysis of function and signaling pathways of DEGs in LUAD was performed by gene ontology (GO) using Enrichr.
Results
CA4 is differentially expressed and downregulated in LUAD tissues compared to normal tissues (P < 0.00). High CA4 expression had favorable overall survival value (HR: 0.67, 95% CI: 0.49 – 0.90, P = 0.0025), and was negatively correlated with the infiltration of myeloid-derived suppressor cells (MDSC) and cancer-associated fibroblasts (spearman’s ρ = -0.397, P < 0.001, ρ = -0.211, P < 0.001, respectively), but positively with macrophage M2 cells and CD8+ (ρ = 0.199, P < 0.001, ρ = 0.154, P < 0.001, respectively). In addition, survival analysis based on CA4 expression and MDSC levels revealed a better OS group identified by high CA4 expression and low MDSC levels after adjustment for age, stage, and tumor purity (P < 0.05). TMB count was inversely associated with CA4 expression (ρ = -0.12, P = 0.007). CA4 promoter methylation level was significantly hypermethylated in LUAD. GO analysis showed that genes positively co-expressed with CA4 were mainly located in specific granules, and mainly participated in biological processes of neutrophil degranulation by molecular function such as G protein-coupled receptor activity.
Conclusions
Our results imply that low expression of CA4 is an indicator of poor prognosis in LUAD patients which might be explained by the associated immune suppressive microenvironment, supporting its potential as a therapeutic target. Moreover, aberrant promoter methylation might explain CA4 downregulation by causing transcription inhibition.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosure
All authors have declared no conflicts of interest.