Abstract B037: Expression of MRTFA facilitates an immunosuppressive tumor microenvironment via upregulation of VSIR
Authors: Lee Kihak , Wilk Stephanie M. , Gajda Alexa M. , Haloul Mohamed , Macias Virgilia , Wiley Elizabeth L. , Chen Zhengjia , Liu Xinyi , Wang Xiaowei , Sverdlov Maria , Hoskins Kent F. , Er Ekrem Emrah 
Published: November 2024

Breast cancer, the second highest cause of cancer-related deaths in women, accounts for 31% of female cancer diagnoses. African American women have lower survival rates than White American women, influenced by both biological factors (age, family history, genetic factors, tumor biology) and social determinants (socio-economic status, insurance status, health care access). However, precise biological determinants remain unclear. The primary reason for breast cancer mortality is metastasis to organs like the lung, liver, and brain, with transcription factors playing a key role in this process. Myocardin related transcription factor A/B (MRTFA/B) are co-activators of serum-response factor (SRF), and the MRTF-SRF complex promotes breast cancer cell migration, invasion, and metastasis by regulating genes involved in actin cytoskeleton remodeling. MRTFA also supports tumor growth by modulating cancer-associated fibroblasts (CAFs) and remodeling the extracellular matrix (ECM) in the tumor microenvironment. While the pro-metastatic role of MRTFA/B is established in vitro and in mice, their impact on human cancer progression and metastasis requires further investigation. Therefore, understanding MRTFA's role in breast cancer metastasis is crucial for improving patient outcomes, making it essential to investigate MRTFA/B expression patterns in both tumor cells and the tumor microenvironment (TME). To explore the clinical, demographic, tumor-intrinsic, and tumor microenvironmental patterns of MRTFA/B’s expression and activation, we utilized multiplex imaging methods on multiple racially diverse tissue microarrays (TMA) and bioinformatics analyses of The Cancer Genome Atlas (TCGA), Molecular Taxonomy of Breast Cancer International Consortium (METABRIC), and available single-cell RNA sequencing datasets. Strikingly, MRTFA expression levels were higher in African American patients than in White American patients. Next, we investigated MRTFA expression patterns in the TME by using single-cell sequencing databases and found more abundant MRTFA expression in dendritic cells (DCs) within the TME compared to any other cell subtype. Moreover, our multiplex-imaging of tumor microarray (TMA) samples showed prominent MRTFA expression in HLA-DRA+CD45+ cells, indicative of antigen-presenting cells (APC). Notably, public single-cell RNA sequencing data indicated that breast cancer DCs strongly express the V-set immunoregulatory receptor (VSIR), an immune checkpoint protein, implying the immunosuppressive nature of the TME and we found that this increased VSIR expression is mediated by the MRTF-SRF complex. These findings suggest that DCs expressing MRTFA in breast cancer microenvironment contribute to creating the immunosuppressive TME via upregulation of VSIR expression, resulting in racial breast cancer disparities.

Citation Format: Kihak Lee, Stephanie M. Wilk, Alexa M. Gajda, Mohamed Haloul, Virgilia Macias, Elizabeth L. Wiley, Zhengjia Chen, Xinyi Liu, Xiaowei Wang, Maria Sverdlov, Kent F. Hoskins, Ekrem Emrah Er. Expression of MRTFA facilitates an immunosuppressive tumor microenvironment via upregulation of VSIR [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr B037.