Pan-Cancer Interrogation of B7-H3 (CD276) as an Actionable Therapeutic Target Across Human Malignancies.

Autor:	Miller CD; Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota., Lozada JR; Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota., Zorko NA; Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota., Elliott A; Caris Life Sciences, Phoenix, Arizona., Makovec A; Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota., Radovich M; Caris Life Sciences, Phoenix, Arizona., Heath EI; Karmanos Cancer Institute, Detroit, Michigan., Agarwal N; Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah., Mckay RR; University of California San Diego, La Jolla, California., Garje R; Miami Cancer Institute, Baptist Health South Florida, Miami, Florida., Bastos BR; Miami Cancer Institute, Baptist Health South Florida, Miami, Florida., Hoon DSB; Saint John's Cancer Institute PHS, Santa Monica, California., Orme JJ; Mayo Clinic Comprehensive Cancer Center, Rochester, Minnesota., Sartor O; Mayo Clinic Comprehensive Cancer Center, Rochester, Minnesota., VanderWalde A; Caris Life Sciences, Phoenix, Arizona., Nabhan C; Caris Life Sciences, Phoenix, Arizona., Sledge G; Caris Life Sciences, Phoenix, Arizona., Shenderov E; The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, Maryland., Dehm SM; Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota.; Departments of Laboratory Medicine and Pathology and Urology, University of Minnesota, Minneapolis, Minnesota., Lou E; Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota., Miller JS; Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota., Hwang JH; Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota., Antonarakis ES; Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota.
Jazyk:	angličtina
Zdroj:	Cancer research communications [Cancer Res Commun] 2024 May 30; Vol. 4 (5), pp. 1369-1379.
DOI:	10.1158/2767-9764.CRC-23-0546
Abstrakt:	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. Significance: B7-H3-targeting therapeutics have shown promising results in initial clinical trials. In this pan-cancer analysis of B7-H3 mRNA expression, we found that B7-H3 exhibits robust expression in many common cancer types. These results may inform further development of B7-H3-targeting therapeutics and may guide clinical decisions for patients with limited treatment options. (© 2024 The Authors; Published by the American Association for Cancer Research.)
Databáze:	MEDLINE
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