AUTHOR=Zhao Bohui , Huang Zehao , Zhu Xinyi , Cai Huizhu , Huang Yingcheng , Zhang Xiwei , Zhang Zongmin , Lu Haizhen , An Changming , Niu Lijuan , Li Zhengjiang 

TITLE=Clinical Significance of the Expression of Co-Stimulatory Molecule B7-H3 in Papillary Thyroid Carcinoma

JOURNAL=Frontiers in Cell and Developmental Biology

VOLUME=Volume 10 - 2022

YEAR=2022

URL=https://www.frontiersin.org/journals/cell-and-developmental-biology/articles/10.3389/fcell.2022.819236

DOI=10.3389/fcell.2022.819236

ISSN=2296-634X

ABSTRACT=<p><bold>Background:</bold> B7-H3, also known as CD276, an important immune checkpoint member of the B7-CD28 family, is confirmed as a promising target after PD-L1 in clinical trials. Although the overexpression of B7-H3 has been associated with invasive metastatic potential and poor prognosis in multiple types of cancer, nothing is known regarding the expression profiles of B7-H3 in papillary thyroid carcinoma (PTC). In this study, we carried out a large-scale analysis of B7-H3 expression in PTC patients and evaluated the potential clinical significance of B7-H3.</p><p><bold>Methods:</bold> In total, data from 1,210 samples, including 867 cases from TCGA and four GEO datasets, were collected for B7-H3–related transcriptome analyses, and 343 postoperative, whole-tumor sections were collected from patients with PTC at our institute for B7-H3–specific immunohistochemistry (IHC) staining. The statistical analysis was primarily accomplished using the R project for statistical computing.</p><p><bold>Results:</bold> B7-H3 positivity was found in 84.8% of PTC patients (291/343), and the mRNA and protein expression levels of B7-H3 in PTC were markedly higher than those of para-tumor tissues (<italic>p</italic> &lt; 0.001), demonstrating that B7-H3 can serve as a potential diagnostic biomarker for PTC. The significant upregulation of B7-H3 in PTC is caused by distinct patterns of CNVs and CpG DNA methylation. Functional enrichment analysis confirmed that high B7-H3 expression was significantly associated with specific immune features and angiogenesis. High B7-H3 protein expression was associated with tumor size (<italic>p</italic> = 0.022), extrathyroidal extension (ETE) (<italic>p</italic> = 0.003), and lymph node metastasis (LNM) (<italic>p</italic> &lt; 0.001). More importantly, multivariate analysis confirmed that B7-H3 was an independent predictor of relapse-free survival (RFS) (<italic>p</italic> &lt; 0.05). In the subgroup analysis, positive B7-H3 staining was associated with worse RFS in patients with primary tumor size ≥2 cm (<italic>p</italic> &lt; 0.05), age ≥55 years (<italic>p</italic> &lt; 0.05), LNM (<italic>p</italic> = 0.07), multifocality (<italic>p</italic> &lt; 0.05), and ETE (<italic>p</italic> &lt; 0.05). In addition, Circos plots indicated that B7-H3 was significantly associated with other immune checkpoints in the B7-CD28 family.</p><p><bold>Conclusion:</bold> This is the first comprehensive study to elucidate the expression profile of B7-H3 in PTC. Our observations revealed that B7-H3 is a novel independent biomarker for predicting LNM and disease recurrence for PTC patients, and it thus may serve as an indicator that could be used to improve risk-adapted therapeutic strategies and a novel target for immunotherapy strategies for patients who undergo an aggressive disease course.</p>