Pan-cancer associations of B7-H3 (CD276) transcriptional expression across human malignancies.
Authors: Hwang Justin , Zorko Nick , Elliott Andrew , Lozada Jose A. , Radovich Milan , Heath Elisabeth I. , Agarwal Neeraj , McKay Rana R. , Garje Rohan , Bastos Bruno R. , Hoon Dave S. B. , Nabhan Chadi , Sledge George W. , Antonarakis Emmanuel S. 
Published: June 2023

2624

Background: B7-H3 ( CD276) is a transmembrane glycoprotein of the B7 superfamily that includes PD-L1 and CTLA-4. B7-H3 targeted therapeutics have demonstrated promising results in both solid tumors and hematologic cancers. To understand the applicability of B7-H3 targeted therapies, we characterized the landscape of clinical outcomes, genomic, transcriptomic, and immunological features associated with B7-H3 mRNA expression in > 93,000 samples across > 45 cancer types from a large real-world clinico-genomics database. Methods: DNA (592-gene/whole exome) and RNA (whole transcriptome) sequencing was performed for samples submitted to Caris Life Sciences (Phoenix, AZ). Differential expression of individual genes was analyzed, with pathway enrichment assessed by Gene Set Enrichment Analyses (GSEA). RNA deconvolution was used to estimate immune cell infiltration of tumor microenvironments using quanTIseq (Finotello, 2019). Real-world overall survival (OS) was determined from insurance claims data and Kaplan-Meier estimates were calculated. Statistical significance was determined using X2 and Mann-Whitney U tests with Benjamini-Hochberg corrections for multiple hypothesis testing where appropriate. Results: B7-H3 mRNA displayed robust expression in many prevalent cancer types, including prostate, pancreatic, breast, colorectal, ovarian, and lung cancers (n = 3407, 4624, 8639, 12,862, 8004, and 13,502, respectively). High B7-H3 expression predicted worse OS in ovarian cancer (1.38 HR, 95% CI 1.23-1.53, p < 0.001) and lung adenocarcinoma (1.45 HR, 95% CI 1.34-1.57, p < 0.001), and better OS in prostate (0.84 HR, 95% CI 0.71-0.99, p < 0.05). Notably, high B7-H3 was detected in tumors with known driver mutations (e.g. EGFR, ESR1, KRAS, SPOP) or undruggable therapeutic targets ( TP53, APC). When examining Hallmark gene signatures, we found that B7-H3-high samples demonstrated consistent enrichment for pathways involved in epithelial to mesenchymal transition (EMT), WNT, TGF-Beta, and Notch signaling (FDR < 0.05) across cancer types. Additionally, high B7-H3 expression was correlated with greater proportions of pro-inflammatory M1 macrophages but lower proportions of effector CD8+ T cells and NK cells across multiple cancer types. Conclusions: We demonstrate B7-H3 to be a promising pan-tumor target, with most solid tumors showing robust expression which is often associated with worse OS. In several major cancers, high B7-H3 expression was associated with mutational and transcriptomic repertoires not easily targeted by current precision therapies. We find B7-H3-high tumors to have increased potential for myeloid-driven immune induction, making them potentially more amenable to immunomodulatory therapies, in particular, those targeting B7-H3. Further work is warranted to elucidate different mechanistic interactions of B7-H3 with specific oncogenic pathways in each cancer type.