Abstract PS4-08: The tumor heterogeneous overexpressed CD155 promotes treatment resistance in HER2-positive breast cancer through immune microenvironment modulation

Abstract Purpose: HER2-positive breast cancer is characterized by high malignancy and frequent recurrence. The combination of immunotherapy with HER2-targeted therapy necessitates a deeper understanding of the immuno-oncology of HER2 breast cancer. CD155, an immune checkpoint highly expressed on tumor cells, promotes tumor growth and interacts with its inhibitory ligand TIGIT to form an immunosuppressive microenvironment. This study investigated the tumor heterogeneous overexpressed CD155 promotes treatment resistance in HER2-positive breast cancer. Methods: We collected 10 untreated human HER2-positive breast cancer scRNA-seq datasets to explore the expression pattern of CD155 and used GSEA and GSVA to characterize epithelial cells expressing high levels of CD155. In addition, 3 paird HER2+ scRNA-seq samples before and after neoadjuvant therapy were also incluced. Based on bulk RNA-seq of HER2 breast cancer from TCGA, we conducted gene co-expression analysis and WGCNA to define the expression network of CD155. To uncover the relationship between CD155 and HER2-targeted therapy resistance, we collected patient tissue microarrays and paired pre/post-treatment samples for IHC. In vitro and in vivo studies were conducted to verify the molecular mechanism of CD155 expression in HER2 breast cancer. Results: Through scRNA-seq from patient samples, we found a strong negative correlation between CD155 and ERBB2 expression in breast cancer cells, with heterogeneous expression further verified in our multiplex IHC of patient samples. To further verify the CD155 high cells are enriched after anti-HER2 treatment, we use neoadjuvant cohorts to evaluate these markers through IHCs and found the upregulation of CD155 post treatment. In addition, based on the TCGA database, CD155 correlates with a worse prognosis only in the HER2-enriched subtype. The relevance between CD155 and worse prognosis was demonstrated in our 200-patient tissue microarray IHC. In scRNA-seq, clusters bearing high expression of CD155 exhibited more vigorous metabolic features. In the cell lines SKBR3 and HCC1954, knockdown CD155 showed a decline in proliferation and increased sensitivity to HER2-targeted therapy. Moreover, Cibersort analysis revealed that CD155 is negatively correlated with the infiltration of activated NK cells in the tumor microenvironment, a major force of the ADCC effect induced by trastuzumab. Conclusion: CD155 plays a critical role in HER2 heterogeneity and mediates immune evasion. Blocking CD155 could be a potent treatment option to overcome resistance to HER2-targeted therapy while preventing NK cell exhaustion and eliciting robust anti-tumor immunity. Citation Format: Yi Zhang, Bingqiu Xiu, Qi Zhang, Jiong Wu. The tumor heterogeneous overexpressed CD155 promotes treatment resistance in HER2-positive breast cancer through immune microenvironment modulation [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr PS4-08.