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

Our plain-English summary of CD276 as a critical independent biomarker and immune checkpoint inhibitor target in epithelioid mesothelioma-TCGA study, by Y. Aoki, K. Arimura, K. Hiroshima, et al (Journal of Thoracic Disease, 2025).

The study

• Authors: Y. Aoki, K. Arimura, K. Hiroshima, Y. Sato, M. Kondo, E. Tagaya
• Journal: Journal of Thoracic Disease
• Published: 2025;17(1):109-120
• Cited by: 2 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

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.

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In plain English

This was a retrospective analysis of public data from The Cancer Genome Atlas (TCGA), a cancer genetics database. The authors examined whether tumor levels of CD276 mRNA, which codes for an immune checkpoint protein, were linked to survival. The mesothelioma analysis covered 86 patients, 57 of them with epithelioid tumors. The study did not examine asbestos exposure. In epithelioid mesothelioma, patients with high CD276 expression had poorer overall survival (hazard ratio 2.864, 95% CI 1.550 to 5.291). After adjusting for age, sex and stage, the hazard ratio was 4.157 (95% CI 2.014 to 8.921). The link held in models that also included the existing drug targets PDCD1, CTLA4 and VEGFA. In biphasic and sarcomatoid mesothelioma combined, the association was not statistically significant (hazard ratio 1.549, 95% CI 0.658 to 3.646). In epithelioid tumors, CD276 expression correlated most strongly with PKM2, a glycolytic pathway gene (r=0.603, 95% CI 0.399 to 0.749, P less than 0.001). The authors concluded that CD276 inhibitors could improve prognosis in epithelioid mesothelioma. They noted the study was retrospective, had limited numbers, and relied on a database.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Retrospective analysis of gene-expression and survival data from a public cancer database (TCGA)
• Who was studied: 86 patients with mesothelioma in TCGA (57 epithelioid, 23 biphasic, 1 sarcomatoid, 5 unknown histology; 70 male, 16 female; mean age 63.1). Other cancer types in TCGA were also analyzed.
• Exposure: High versus low CD276 mRNA expression in tumor tissue. Protein levels were not measured. The study did not examine asbestos or any other exposure; asbestos appears only in the introduction as background.
• Main results:
  • In epithelioid mesothelioma, high CD276 mRNA expression was associated with poorer overall survival (HR 2.864, 95% CI 1.550 to 5.291, P less than 0.001)
  • In biphasic and sarcomatoid mesothelioma analyzed together, high CD276 mRNA expression was not associated with poorer survival (HR 1.549, 95% CI 0.658 to 3.646, P=0.27)
  • In epithelioid mesothelioma, after adjustment for age, sex and stage, high CD276 mRNA expression was associated with worse overall survival (HR 4.157, 95% CI 2.014 to 8.921)
  • In epithelioid mesothelioma, the association with poor survival remained in models that also considered PDCD1, CTLA4 and VEGFA
  • In epithelioid mesothelioma, CD276 mRNA expression correlated weakly with only 3 of 37 markers of tumor-infiltrating immune cells
  • In epithelioid mesothelioma, CD276 expression correlated strongly with PKM2 expression (r=0.603, 95% CI 0.399 to 0.749, P less than 0.001)
  • In a model including six glycolytic gene markers, CD276 expression correlated mostly with PKM2 (beta 0.443, 95% CI 0.087 to 0.799, P=0.01)
• The authors' conclusion: The authors concluded that CD276 is a target for immune checkpoint inhibitors and that CD276 inhibitors could improve prognosis in patients with epithelioid mesothelioma
• Limitations the authors state:
  • The study was retrospective with a limited number of patients; larger prospective studies are needed to validate the results
  • The results came from a clinical database; laboratory and animal studies are needed to clarify CD276's role
  • The dataset did not include PKM1 expression data

Topics

Medical terms in this study, explained in our Lexicon: Biomarker, checkpoint inhibitors, Epithelioid, Mesothelioma, Overall Survival, Prognosis.

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