Abstract PO4-03-13: High B7-H3 expression with low PD-L1 expression identifies armored-cold tumors suggesting potential anti-B7-H3 therapy in triple-negative breast cancer

Abstract Background: Triple-negative breast cancer (TNBC) is generally regarded as the most aggressive subtype among breast cancer. B7 homolog 3 protein (B7-H3), also known as CD276, is an emerging immune checkpoint molecule, which plays a dual role in the immune system. Multiple anti-B7-H3 therapies has been raised, such as DS-7300, MGA271, MGD009, and B7-H3 chimeric antigen receptor T-cell immunotherapy (CAR-T). However, the expression of B7-H3 in TNBC and its value as a biomarker identifying therapeutic options has not been elucidated Methods: A total of 165 samples (83 non-TNBC and 82 TNBC) were included in this study, and 6 samples included paired para-tumor samples. In addition, 30 TNBC patients receiving standardized neoadjuvant chemotherapy (NAT) were recruited. After 8 cycles of NAT, the response to NAT was assessed by RECIST1.1 criterion before surgical operation. Moreover, multiple public cohorts of breast cancer and TNBC were obtained, including the TCGA dataset, the METABRIC dataset, the GSE176307 (durvalumab-based therapy) dataset, the PRJNA558949 (durvalumab-based therapy) dataset, the GSE194040 (paclitaxel-based therapy) dataset, and the GSE34138 (anthracycline-based therapy) dataset. Based on multiple in-house and public cohorts, we investigated the expression features of B7-H3 in breast cancer and checked the anti-tumor effect of the B7-H3 monoclonal antibody in mouse model. We also developed a novel classifier combined B7-H3 and PD-L1 expression in TNBC. Results: B7-H3 was highly expressed in tumor tissues in the in-house and the TCGA cohorts. B7-H3 expression did not differ significantly between non-TNBC and TNBC samples in the in-house and the TCGA cohorts, excepting for the METABIRC cohort. There was no notable difference in CD8+ cells infiltration between B7-H3 low and high expressed non-TNBC samples, but CD8+ cells was notably higher in the B7-H3 low expressed TNBC samples. The similar findings were also observed in the TCGA and the METABIRC cohorts. In addition, enrichment analysis of transcriptome data and analysis of in-house samples showed that B7-H3 was positively related to most collagens. Moreover, anti-B7-H3 therapy significantly inhibited tumor growth in mouse TNBC model, notably increased immune cells infiltration, and also reduced collagen deposition within the tumor. Given the notable value of PD-L1 in predicting immunotherapy responses, we also combined B7-H3 and PD-L1 expression to establish a novel subtyping strategy. TNBC patients with B7-H3highPDL1low feature exhibited the lowest anti-tumor immune infiltration and higher collagen deposition level. In the durvalumab-dependent cohort, paclitaxel-dependent cohort, anthracycline-dependent cohort, and our recruited NAT cohort, the B7-H3highPDL1low subgroup exhibited the lowest therapeutic response. Conclusions: Overall, this research provides a novel subtyping strategy based on the combination of B7-H3/PD-L1 expression that could potentially be applied to predict the therapeutic responses in TNBC, and suggests a potential biomarker-guided anti-B7-H3 therapy. Based on the classifier, we can select potential beneficiaries to deliver personalized medical services. Citation Format: Jie Mei, Yun Cai, Ziyi Fu, Yongmei Yin. High B7-H3 expression with low PD-L1 expression identifies armored-cold tumors suggesting potential anti-B7-H3 therapy in triple-negative breast cancer abstract. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-03-13.