Abstract B053: The role of whole genome doubling in immune escape in TNBC

Abstract

Abstract Triple-negative breast cancers (TNBC) account for 10-15% of all breast cancers. The combination of chemotherapy and immune checkpoint inhibitor (ICI) therapy is now a standard in stage II-III TNBC while this regimen is used only in a subset of advanced TNBC tumors with high expression of PD-L1. Whole exome sequencing of solid tumors (other than breast cancer) in clinical trials investigating ICI determined that tumors which undergone a WGD (whole genome doubling) are more sensitive to immune checkpoints inhibitors, but the underlying mechanisms have not been defined. WGD occurs in 44% of breast cancers and it has been associated with advanced stage, poor survival, and higher risk of resistance to chemotherapies and targeted therapies. However, its role in response to ICI treatment in TNBC has not been investigated. To investigate the functional relevance of WGD in therapeutic responses in TNBC, we generated isogenic cell line pairs (3 murine and 1 human) that are diploid/euploid (WGD-) or tetraploid (WGD+) using somatic cell fusion. To explore the impact of WGD on tumor growth, we injected parental (WGD-) and fusion (WGD+) cells into mammary fat pads of syngeneic immunocompetent or immunocompromised (NSG) mice. We found that while there was no difference in growth between parental (WGD-) and fusion (WGD+) cells in immune deficient mice, in immunocompetent mice tumors derived from fusion (WGD+) cells grew significantly faster compared to parental (WGD-). We have been analyzing differences between parantel and fusion cell-derived tumos using FACS, immunofluorescence, and single cell RNA-seq (scRNA-seq) and found significant immune-related differences implying a more immune suppressive environment in fusion tumors. These data suggest that WGD in TNBC may be a predictor of response to ICI therapies. Citation Format: Pierre Foidart, Zheqi Li, Marco Seehawer, Jun Nishida, Ernesto Rojas, Triet Bui, Pengze Yan, Marie-Anne Goyette, Laura Stevens, Xiao-Yun Huang, Jayati Anand, Gouri Nanjangud, Yingtian Xie, Xintao Qiu, Paloma Cejas, Henry Long, Kornelia Polyak. The role of whole genome doubling in immune escape in TNBC [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Breast Cancer Research; 2023 Oct 19-22; San Diego, California. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_1):Abstract nr B053.