Abstract
B7-H3 (CD276) is a transmembrane glycoprotein of the B7 immune checkpoint superfamily that has emerged as a promising therapeutic target. To better understand the applicability of B7-H3-directed therapies, we analyzed 156,791 samples comprising 50 cancer types to interrogate the clinical, genomic, transcriptomic, and immunologic correlates of B7-H3 mRNA expression. DNA (592-gene/whole-exome) and RNA (whole-transcriptome) sequencing was performed from samples submitted to Caris Life Sciences. B7-H3 high versus low expression was based on top and bottom quartiles for each cancer type. Patients' overall survival was determined from insurance claims data. Pathway analysis was performed using gene set enrichment analyses. Immune cell fractions were inferred using quanTIseq. B7-H3 is expressed across several human malignancies including prostate, pancreatic, ovarian, and lung cancers. High B7-H3 expression is associated with differences in overall survival, possibly indicating a prognostic role of B7-H3 for some cancers. When examining molecular features across all cancer types, we did not identify recurrent associations between B7-H3 expression and genetic alterations in TP53, RB1, and KRAS. However, we find consistent enrichment of epithelial-to-mesenchymal transition, Wnt, TGFβ, and Notch signaling pathways. In addition, tumors with high B7-H3 expression are associated with greater proportions of M1 macrophages, but lower fractions of CD8+ T cells. We have begun to define the genomic, transcriptomic, clinical, and immunologic features associated with B7-H3 expression in 50 cancer types. We report novel clinical and molecular features of B7-H3-high tumors which may inform how current B7-H3 therapeutics should be deployed and prioritized.
Publication Date
5-30-2024
Content Type
Article
PubMed ID:
Citation
Miller, C. D., Lozada, J. R., Zorko, N. A., Elliott, A., Makovec, A., Radovich, M., Heath, E. I., Agarwal, N., Mckay, R. R., Garje, R., Bastos, B. R., Hoon, D. S. B., Orme, J. J., Sartor, O., VanderWalde, A., Nabhan, C., Sledge, G., Shenderov, E., Dehm, S. M., Lou, E., … Antonarakis, E. S. (2024). Pan-Cancer Interrogation of B7-H3 (CD276) as an Actionable Therapeutic Target Across Human Malignancies. Cancer research communications, 4(5), 1369–1379. https://doi.org/10.1158/2767-9764.CRC-23-0546
Comments
This open access article is distributed under the Creative Commons Attribution 4.0 International (CC BY 4.0) license. © 2024 The Authors; Published by the American Association for Cancer Research