Abstract C111: Spatial transcriptome profiling of tumor and tumor microenvironment of triple negative breast cancer in patients of African American and European American descent
Authors: Bedi Deepa , Karanam Balasubramanyam , Elhussin Isra , Nayak Chitra R. , Yates Clayton 
Published: January 2023

Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype that disproportionately affects women of African origin. AA women with TNBC have worse clinical outcomes than women of European descent as it presents with a more aggressive and progressive disease. Understanding the underlying biology of the tumor and its microenvironment is critical to address the disparity associated with racial differences in breast cancer. Bulk RNA-sequencing is the most common and useful method to analyze whole transcriptome. However, this method cannot deconvolute the individual components of the tumor and its associated stroma. The NanoString GeoMx digital spatial profiling is a multiplexed platform that spatially resolves and quantifies the abundance of genes present in tumor and stroma. In this study, we have utilized spatial RNA-seq technology to determine the differential gene expression in tumor epithelial cells and its associated stroma in AA and EA TNBC patients. Gene expression from spatially defined regions in tumor and stroma in each patient and in between races identified distinct molecular pathways. The tumor epithelial region of AA has high expression of fatty acid biosynthesis, nucleotide excision repair, RNA helicase like proteins and exhaustion signaling while EA tumor epithelial region had high expression of neuropilin 2, interferon signaling and TGF beta signaling. The pathways overexpressed in the AA stromal region included tryptophan metabolism, chemokine signaling pathway, interferon signaling and exhaustion signature while in the EA stromal region, the pathways pertinent to mTOR signaling, AURORA kinase, cysteine endopeptidases were more prominently expressed. AA tumors were significantly more inflamed than EA and exhibited high infiltration of immune cells. The stromal region of AA tumors has high population of macrophages, CD8 T memory, Treg’s and neutrophils more than EA tumors. The tumor epithelial region of AA has high infiltration of plasmacytoid dendritic cells (pDC), B memory, monocytes, natural killer cells (NK), CD4 memory, CD4 naïve, Treg’s and plasma cells. However, the exhaustion signature proteins, PDCD1 and LAG3 were also higher in tumor-infiltrated and stromal immune cells in AA tumor. The EA tumors were scarce in immune cells in the stroma as well as inside the tumor epithelial, though interferon signaling was substantially higher in EA tumor epithelial cells as compared to AA. Thus, using NanoString GeoMx digital spatial profiling platform, we have spatial profiled AA and EA TNBC and assessed the inter and intra-tumor heterogeneity within and in between races. This is one of the first study that describes not only expression variation of genes between races but also between stroma and tumor epithelial cells within the tissue of same patient and between different patients. These findings address the biological determinant of racial disparity by patient-centered investigation of factors associated with tumor and tumor microenvironment.

Citation Format: Deepa Bedi, Balasubramanyam Karanam, Isra Elhussin, Chitra R. Nayak, Clayton Yates. Spatial transcriptome profiling of tumor and tumor microenvironment of triple negative breast cancer in patients of African American and European American descent [abstract]. In: Proceedings of the 15th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2022 Sep 16-19; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr C111.