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FIGURE 3 from Pan-Cancer Interrogation of B7-H3 (CD276) as an Actionable Therapeutic Target Across Human Malignancies

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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

Independence of B7-H3 expression and immunotherapy biomarkers. Alteration frequency of TMB-high (A), MSI-high (B), MMRd (C), and PD-1/ PD-L1 status (D) across 11 different cancer types with high and low B7-H3 expression, including prostate cancer from a primary site (PRAD-Prostate), prostate cancer from a metastatic site (PRAD-Metastatic), colorectal cancer with microsatellite stability (CRC-MSS), colorectal cancer with microsatellite instability (CRC-MSI), non–small cell lung adenocarcinoma (NSCLC-Ad), non–small cell lung squamous carcinoma (NSCLC-Sq), triple-negative breast cancer (BRCA-TNBC), hormone receptor–positive/HER2-negative breast cancer (BRCA-HR+/HER2−), HER2-positive breast cancer (BRCA-HER2+), ovarian surface epithelial carcinoma (OSEC), and pancreatic carcinoma (PDAC). *, q < 0.05; **, q < 0.01; ***, q < 0.001. Cox proportional HRs were calculated for each comparison group with significance determined as q values of <0.05 using log-rank statistics.

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.