CD276 as a critical independent biomarker and immune checkpoint inhibitor target in epithelioid mesothelioma-TCGA study.

Abstract

Background: CD276 is an immune checkpoint, and immune checkpoint inhibitors (ICIs) targeting CD276 have been tested against various cancers. However, the precise role of CD276 in mesothelioma subtypes is unknown. This study aimed to reveal the prognostic significance of CD276 in various cancers and explore CD276 as a target for ICIs in different mesothelioma subtypes.

Methods: We evaluated data from The Cancer Genome Atlas (TCGA) database retrospectively. The Wilcoxon rank-sum test was used to assess CD276 mRNA expression between cancer tissues and the adjacent normal tissues in the context of various cancers. The study involved 86 patients with mesothelioma. The mean number of patients was set as the cutoff value for comparing CD276 mRNA expression. The overall survival (OS) of patients with each mesothelioma subtype was estimated using the Kaplan-Meier method with CD276 mRNA expression. The factors affecting the correlation between OS and high/low CD276 expression in combination with/without a current existing molecular targets of programmed cell death 1 (PD-1), cytotoxic T-lymphocyte-associated protein 4 (CTLA4), and vascular endothelial growth factor A (VEGFA) were assessed using a multivariate Cox proportional hazards model. The correlation between the mRNA expression of CD276 and expression of gene markers of tumor-infiltrating immune cells and those of different pathways was evaluated using Spearman's correlation. The factors affecting correlations of CD276 mRNA expression were confirmed using a multivariate linear regression model.

Results: Upregulated CD276 mRNA expression was associated with a poor prognosis in various cancers, including epithelioid mesothelioma. The multivariate Cox proportional hazards model demonstrated that upregulated CD276 mRNA expression indicated the worst prognosis, including the combination of CD276 and PD-1, CTLA4, and VEGFA. In addition, using a multivariate linear regression model, CD276 mRNA expression was found to correlate with multiple glycolytic pathway mRNAs in epithelioid mesothelioma, especially PKM2.

Conclusions: CD276 is an independent prognostic biomarker in patients with epithelioid mesothelioma. It is associated with the glycolytic pathway and may contribute to ATP generation in epithelioid mesothelioma. CD276 inhibitors might contribute to better prognosis in patients with epithelioid mesothelioma.