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

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.

FIGURE 1

Characterization of B7-H3 expression in tumors. B7-H3 transcripts per million (TPM) after log normalization. A total of 156,791 samples from 50 distinct tumor types were analyzed from the Precision Oncology Alliance (POA) consortium. Data shown in violin plots in which the white dot represents the median and the black box shows the ends of the first and third quartiles. The female genital tract malignancy category represents sarcomas from gynecologic sites and the male genital tract malignancy category represents primarily testicular cancer.

FIGURE 2

Tumor profile association with OS. A, Association of OS in tumors with the top 75th percentile of B7-H3 expression (relative to all cancers) across 50 tumor types. *, q < 0.05; **, q < 0.01; ***, q < 0.001. 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 P values of <0.05 using log-rank statistics. C, 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.

FIGURE 3

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.

FIGURE 4

B7-H3 expression and immune cell landscape. Immune cell deconvolution using quanTIseq demonstrates differences in cell fraction of T cells CD8⁺ (A), macrophage M1 (B), and macrophage M2 (C) across 10 different cancer types with high and low B7-H3 expression. *, q < 0.05; **, q < 0.01; ***, q < 0.001.

FIGURE 5

Association of B7-H3 expression with key driver mutations. Alteration frequency of TP53 mutations (A), RB1 mutations (B), KRAS mutations (C), MYC amplifications (D) of across 10 different cancer types with high and low B7-H3 expression. **, 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.

FIGURE 6

Association of B7-H3 expression and common hallmark mRNA signatures. GSEA with functional oncogenic pathways on several tumor types with high and low B7-H3 expression. Normalized enrichment scores are displayed. FDR < 0.05 based on values between −3 and 3. Boxes marked with “X” indicate that the enrichment of the pathway did not meet thresholds of significance in the tumor type.