TFAP2A-activated ITGB4 promotes lung adenocarcinoma progression and inhibits CD4+/CD8+ T-cell infiltrations by targeting NF-κB signaling pathway.

Abstract

Background: Immune-associated genes play vital roles in the tumorigenesis, progression and immunotherapy responses of malignant tumors. This study aimed to comprehensively evaluate the role and mechanism of novel immune-associated gene integrin β4 (ITGB4) in the progression and immune microenvironment of lung adenocarcinoma (LUAD).

Methods: There were 770 immune-associated genes curated from NanoString PanCancer Immune Profiling Panel. Differentially expressed immune-related genes were initially screened using transcriptome data from 57 paired LUAD samples in The Cancer Genome Atlas (TCGA) and 15 paired LUAD samples in GSE31210, and were further validated in 19 paired LUAD samples from our institution. Log-rank test was adopted to identify LUAD prognosis associated genes. Among the identified differentially expressed genes, ITGB4 was ultimately chosen for further analysis. Subsequently, the functionality and mechanisms of ITGB4 were investigated in two LUAD cell lines, A549 and PC9, which exhibited relatively high expression levels of ITGB4. Following this, the impact of ITGB4 on the proliferation and metastasis of LUAD in vivo was evaluated using nude mice. Additionally, its effect on T cell infiltration was studied using immunocompetent C57BL/6J mice.

Results: ITGB4 was found to be significantly up-regulated in LUAD and associated with an unfavorable prognosis. Functionally, ITGB4 could promote LUAD cell proliferation, migration and invasion. Consistently, in vivo experiments demonstrated that ITGB4 knockdown suppressed LUAD tumor growth and metastasis. Additionally, ITGB4 could suppress CD4⁺ and CD8⁺ T-cell infiltrations in LUAD cells. Mechanistically, ITGB4 could activate the NF-κB signaling pathway by interacting with IκBα. Furthermore, TFAP2A could directly bind to the ITGB4 promoter and transcriptionally activate ITGB4 in LUAD cells. In addition, laminin-5, a ligand of ITGB4, was found to promote LUAD progression by activating the ITGB4 signaling.

Conclusions: ITGB4 was transcriptionally activated by TFAP2A, and could promote LUAD progression and inhibit CD4⁺/CD8⁺ T-cell infiltrations by activating the NF-κB signaling pathway. ITGB4 may serve as a potential immunotherapeutic target of LUAD.