AUTHOR=Wen Yang , Lin Anqi , Zhu Weiliang , Wei Ting , Luo Peng , Guo Linlang , Zhang Jian 

TITLE=Catenin Alpha-2 Mutation Changes the Immune Microenvironment in Lung Adenocarcinoma Patients Receiving Immune Checkpoint Inhibitors

JOURNAL=Frontiers in Pharmacology

VOLUME=Volume 12 - 2021

YEAR=2021

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2021.645862

DOI=10.3389/fphar.2021.645862

ISSN=1663-9812

ABSTRACT=Background: Lung cancer has always been the most prevalent cancer. Lung adenocarcinoma (LUAD) is the most common lung cancer subtype and has a high tumor mutation rate. In addition to KRAS, EGFR, ALK, HER2, ROS1, and BRAF, we discovered some new mutated genes, such as catenin alpha-2 (CTNNA2), in LUAD patients treated with immune checkpoint inhibitors (ICIs). 
Methods: We analyzed a cohort of LUAD patients  in the Cancer Genome Atlas (TCGA) database and a cohort of LUAD patients receiving immune checkpoint inhibitors to evaluate the role of CTNNA2 gene mutation in LUAD. In addition, CIBERSORT was used to analyze the immune characteristics of CTNNA2 wild-type patients and CTNNA2 mutant-type patients, and gene set enrichment analysis (GSEA) was employed for pathway enrichment analysis. The results were verified by downloading data regarding the drug sensitivity of LUAD cell lines from the Genomics of Drug Sensitivity in Cancer (GDSC) database.
Results: We found that CTNNA2 mutation was associated with longer overall survival (OS) in LUAD patients. Analysis of the cohort from TCGA showed that patients with CTNNA2 mutation had more tumor neoantigens and a greater tumor mutation burden (TMB). Through further analysis of the tumor immune microenvironment, we found that in LUAD patients with CTNNA2 mutations, the gene expression levels of chemokine C-X-C motif chemokine 9 (CXCL9) and granzyme B (GZMB) were elevated, and the gene expression level of inhibitory receptor killer cell immunoglobulin-like receptor 2DL1 (KIR2DL1) was significantly reduced. These alterations might affect gene expression in macrophages, NK cells, and mast cell markers. In addition, LUAD patients with CTNNA2 mutation had a significantly increased number of mutations in DNA damage response (DDR) genes. The drug susceptibility results and GSEA showed that after CTNNA2 mutation occurred, changes were found in the DDR pathway, the phosphoinositide 3-kinase (PI3K) pathway and others, indicating that CTNNA2 mutation can regulate the activation of PI3K and DDR pathways.
Conclusion: Our findings provide novel insights into the underlying pathogenesis of LUAD. The results suggest that CTNNA2 may become a new biomarker and therapeutic target for LUAD in the future.