Multi-omics analyses of CD276 in pan-cancer reveals its clinical prognostic value in glioblastoma and other major cancer types

Abstract

Background CD276 (also known as B7-H3) is one of the most important immune checkpoints of the CD28 and B7 superfamily, and its abnormal expression is closely associated with various types of cancer. It has been shown that CD276 is able to inhibit the function of T cells, and that this gene may potentially be a promising immunotherapy target for different types of cancer. Methods Since few systematic studies have been published on the role of CD276 in cancer to date, the present study has employed single-cell sequencing and bioinformatics methods to analyze the expression patterns, clinical significance, prognostic value, epigenetic alterations, DNA methylation level, tumor immune cell infiltration and immune functions of CD276 in different types of cancer. In order to analyze the potential underlying mechanism of CD276 in glioblastoma (GBM) to assess its prognostic value, the LinkedOmics database was used to explore the biological function and co-expression pattern of CD276 in GBM, and Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed. In addition, a simple validation of the above analyses was performed using reverse transcription-quantitative (RT-q)PCR assay. Results The results revealed that CD276 was highly expressed, and was often associated with poorer survival and prognosis, in the majority of different types of cancer. In addition, CD276 expression was found to be closely associated with T cell infiltration, immune checkpoint genes and immunoregulatory interactions between lymphoid and a non-lymphoid cell. It was also shown that the CD276 expression network exerts a wide influence on the immune activation of GBM. The expression of CD276 was found to be positively correlated with neutrophil-mediated immunity, although it was negatively correlated with the level of neurotransmitters, neurotransmitter transport and the regulation of neuropeptide signaling pathways in GBM. It is noteworthy that CD276 expression was found to be significantly higher in GBM compared with normal controls according to the RT-qPCR analysis, and the co-expression network, biological function and chemotherapeutic drug sensitivity of CD276 in GBM were further explored. In conclusion, the findings of the present study have revealed that CD276 is strongly expressed and associated with poor prognosis in most types of cancer, including GBM, and its expression is strongly associated with T-cell infiltration, immune checkpoint genes, and immunomodulatory interactions between lymphocytes and non-lymphoid cells. Conclusions Taken together, based on our systematic analysis, our findings have revealed important roles for CD276 in different types of cancers, especially GBM, and CD276 may potentially serve as a biomarker for cancer.

Treatment advances in high-grade gliomas

“…Based on the CGGA and TCGA projects, B7-H3 has been found to be upregulated in higher grade gliomas compared to lower grade gliomas ( 121 ). Furthermore, a recent multi-omics analysis reported high B7-H3 expression in multiple cancer types and correlated this upregulation with poorer survival and prognosis ( 122 ). Additionally, B7-H3 expression was found to be significantly elevated in GBM compared with normal controls ( 122 ).…”

“…Furthermore, a recent multi-omics analysis reported high B7-H3 expression in multiple cancer types and correlated this upregulation with poorer survival and prognosis ( 122 ). Additionally, B7-H3 expression was found to be significantly elevated in GBM compared with normal controls ( 122 ). Nonetheless, further preclinical studies and clinical data are needed to elucidate the role of B7-H3 in glioma.…”

Current Landscape of Cancer Immunotherapy: Harnessing the Immune Arsenal to Overcome Immune Evasion

“…Although in mouse models B7-H3 expression on tumor cells has demonstrated NK/CD8-mediated tumor regression, such evidence is seldom found in humans. Instead, clinical and preclinical data demonstrate an association between CD276 expression and poor prognosis, reduced TILs infiltration, impaired anti-tumor responses by CD8 + T cells and NK cells, as well as heightened metastasis across several cancer types, such as pancreatic, esophageal, and cervical cancer [127][128][129][130]. In NSCLC, it is also associated with active Treg infiltration [131].…”

The bispecific B7H3xCD3 antibody CC-3 induces T cell immunity against bone and soft tissue sarcomas

“…The identification of B7-H3/CD276 expressed by many sarcoma subtypes despite their heterogeneity, fueled interest in this molecule as a target for sarcoma treatment (24-26). In addition, B7-H3 is also expressed on the neovasculature of tumors (25,27). To target B7-H3 for cancer treatment, we recently developed an optimized bsAb termed CC-3 (28,29).…”