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posted on 2024-05-30, 14:20 authored by 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 <p>Tumor profile association with OS. <b>A,</b> Association of OS in tumors with the top 75th percentile of B7-H3 expression (relative to all cancers) across 50 tumor types. *, <i>q</i> < 0.05; **, <i>q</i> < 0.01; ***, <i>q</i> < 0.001. <b>B,</b> OS of patients with high B7-H3 expression compared with low B7-H3 expression (stratified on the basis of medians) for the top six cancers where CD276-high expression is associated with poor OS. Cox proportional HRs were calculated for each comparison group with significance determined as <i>P</i> values of <0.05 using log-rank statistics. <b>C,</b> OS of patients with high B7-H3 expression compared with low B7-H3 expression (stratification based on quartiles) from the start of pembrolizumab treatment for patients with colorectal cancer with microsatellite instability (CRC-MSI-H), NSCLC-adenocarcinoma (NSCLC-Ad) that is PD-L1–positive/EGFR wildtype/ALK wildtype, and NSCLC-squamous (NSCLC-Sq) cell carcinoma that is PD-L1 positive.</p>
Funding
HHS | National Institutes of Health (NIH)
American Society of Hematology (ASH)
U.S. Department of Defense (DOD)
Prostate Cancer Foundation (PCF)
University of Minnesota Institute for Prostate and Urologic Cancers Philanthropic Fund
Randy Shaver Community Cancer Fund
HHS | NIH | National Cancer Institute (NCI)
History
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.
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.
