ITGAX is associated with poor prognosis and an immune-inflammatory microenvironment in clear cell renal cell...

Integrin alpha X (ITGAX, CD11c) functions as a leukocyte adhesion molecule vital for immune cell activation, antigen presentation, and inflammatory responses. However, the expression profile, clinical relevance, immunoregulatory functions, and underlying mechanisms of ITGAX in clear cell renal cell carcinoma (ccRCC) remain incompletely elucidated.

ITGAX expression and its association with clinicopathological characteristics were examined using The Cancer Genome Atlas (TCGA)-kidney renal clear cell carcinoma (KIRC) dataset. Survival outcomes were analyzed using Kaplan-Meier and Cox regression methodologies. However, diagnostic efficacy was assessed via receiver operating characteristic (ROC) curve analysis. Immune cell infiltration, tumor purity, and immune checkpoint gene expression were evaluated using various computational algorithms. To elucidate the molecular features associated with ITGAX, functional enrichment and protein-protein interaction analyses were conducted. A KIRC single-cell RNA sequencing dataset was used to ascertain the cellular localization of ITGAX within the tumor microenvironment. In vitro validation involved the use of the ccRCC cell lines 786-O and Caki-1, alongside the normal renal epithelial cell line HK-2. ITGAX knockdown, functional assays, Western blotting, and AKT reactivation with SC79 were used to study cell phenotypes and the AKT/mTOR signaling pathway.

ITGAX expression was markedly upregulated in TCGA-KIRC tissues and positively correlated with adverse clinicopathological characteristics, poorer overall survival, and favorable diagnostic efficacy, as evidenced by ROC curve analysis. Various computational algorithms indicated a strong association between ITGAX expression and immune cell infiltration, reduced tumor purity, elevated immune scores, and increased immune checkpoint gene expression. Functional enrichment analysis revealed that genes associated with ITGAX were predominantly involved in immune-related and microenvironment-associated pathways. Single-cell analysis demonstrated that ITGAX was predominantly enriched in myeloid cell populations, particularly monocytes/macrophages and dendritic cells, within the KIRC tumor microenvironment. In vitro experiments confirmed the relative elevation of ITGAX in ccRCC cell lines compared to HK-2 cells and revealed that ITGAX knockdown led to reduced cell proliferation, migration, invasion, and clonogenicity. ITGAX silencing was also associated with decreased AKT/mTOR phosphorylation, whereas AKT reactivation partially mitigated these phenotypic changes.

This study suggests that ITGAX is associated with unfavorable clinical characteristics, a myeloid-enriched immune contexture, and AKT/mTOR-associated malignant phenotypes in ccRCC. These results suggest that ITGAX is a potential immune-related biomarker of ccRCC; however, additional clinical, spatial, and in vivo validation is necessary.