Spatially resolved cell type heterogeneity uncovers the distinct biology of inflammatory breast cancer

Abstract Inflammatory breast cancer (IBC) is the most lethal form of breast cancer due to rapid progression, distinct morbidity due to pain, swelling, infection and eventual death. It accounts for 10% of all breast cancer caused deaths despite being only 2-4% of all breast cancer diagnosis. Histopathologically, scattered tumor emboli and dermal lymphatic invasion are typical histopathological findings of IBC, shown in about 75% of all IBC cases. However, the etiology of this disease remains largely unknown and its diagnostic difficult to establish.Using single cell transcriptomics, we profiled a total of 10 patient-derived needle biopsies from IBC-hormone receptor (IBC-HR), IBC-triple negative breast cancer (IBC-TNBC), TNBC and HR subtypes, and one normal breast sample. After data QC, we obtained a total of 36,000 cells representing immune, epithelial and stromal cell populations. We performed analysis of the spatial cell distribution through a transcriptomics-informed panel using highly multiplex imaging mass cytometry (IMC) on FFPE section obtained from the same patients.While we noted interpatient heterogeneity within cancer cells in our single cell dataset, immune and stromal cells did show similarity across IBC patients. We identified differences across the myeloid compartment between IBC and non-IBC cells, specifically affecting the dendritic cell subpopulations.The interferon gamma pathway was specifically elevated in several cell types across IBC patients, and particularly in immune cells such as T and myeloid cells. We used MX1 as a marker of interferon gamma response as part of the IMC panel and confirmed this signature in IBC samples. There was no alpha and beta interferon transcriptomic signature in the single cells. Through IMC, we were able to identify the cellular composition surrounding the tumor microemboli. Contrary to what has been postulated in the literature, these cells are not lymphatic cells, but appear to be of fibroblastic origin and express the fibroblast marker CD90. As well, we detected a non-overlapping distribution of Collagen 1 positive and CD90 positive fibroblasts throughout the IBC specimens, revealing heterogeneity within the fibroblast population and its organization. Spatial immune cell analysis also revealed the presence of tertiary lymphoid structures in IBC tumors. Citation Format: Elise Courtois, William Flynn, Santhosh Sivajothi, Martine Seignon, Diane Luo, Bora Lim, Paul Robson. Spatially resolved cell type heterogeneity uncovers the distinct biology of inflammatory breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-24-04.