Pan-Cancer Interrogation of B7-H3 ( CD276 ) as an Actionable Therapeutic Target Across Human Malignancies
Year: 2024
Type: article
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. 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.
Source: Cancer Research Communications
Authors: Carly D. Miller, John R. Lozada, Nicholas A. Zorko, Andrew Elliott, Allison Makovec, Milan Radovich, Elisabeth I. Heath, Neeraj Agarwal, Rana R. Mckay, Rohan Garje, Bruno R. Bastos, Dave S.B. Hoon, Jacob J. Orme, Oliver Sartor, Ari VanderWalde, Chadi Nabhan, George Sledge, Eugene Shenderov, Scott M. Dehm, Emil Lou, Jeffrey S. Miller, Justin H. Hwang, Emmanuel S. Antonarakis
Institutions: University of Minnesota, Masonic Cancer Center, Caris Life Sciences (United States), The Barbara Ann Karmanos Cancer Institute, University of Utah, Huntsman Cancer Institute, University of California San Diego, Baptist Health South Florida, Saint John's Health Center, Mayo Clinic, Mayo Clinic Comprehensive Cancer Center (Minnesota), Johns Hopkins University, Johns Hopkins Medicine, Sidney Kimmel Comprehensive Cancer Center
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $2,550
Funders: U.S. Department of Defense, Prostate Cancer Foundation, American Society of Hematology, Bristol-Myers Squibb, Eli Lilly and Company, Pfizer, Sanofi, Gilead Sciences, University of Minnesota, Exelixis, Celldex Therapeutics, Eisai, Astellas Pharma, Bavarian Nordic, National Institutes of Health, Genentech, EMD Serono, National Cancer Institute, National Institute of General Medical Sciences
Awards: G1182955057, G1345980661, G1905428511, G2915001239, G3346609565, G345720138, DOD PCRP CLINICAL CONSORTIUM AWARD, G4103018608, G4119534169, G4838815, G5700729068, G5850682332, G5926790321, UTILIZATION OF GENETICALLY ENGINEERED NATURAL KILLER CELLS TO SECRETE BISPECIFIC IMMUNE ENGAGER MOLECULES IN THE PROSTATE TUMOR MICROENVIRONMENT, G9000056272, G9000249913, G9000278143, Cancer Center Support Grant, Targeting off-the-shelf iPSC-derived natural killer cells against solid tumors
OpenAlex ID: W4396677030