Abstract 6167: Defining the role of transcriptional coregulator MED15 in immune adaptation in cancer

Abstract The immune system is widely recognized as an important regulator of cancer progression and metastasis, where immune cells can actively promote or inhibit tumor growth. Initially, immune cells act to eradicate cells with emerging cancerous properties, but cancer cells reprogram these immune cells to instead help promote growth of the cancer. Modulating the immune system is therefore an important approach in cancer therapy, however, the identification of new molecular targets is still needed. A potential target includes MED15, a subunit of the transcriptional coregulator complex Mediator, which interacts with transcription factors (TFs) bound to gene regulatory elements. MED15 upregulation occurs in several cancers and is associated with aggressive clinical presentation and shorter patient survival. The precise role that MED15 plays in immune responses in cancer, however, is not known. To investigate this, MED15KO A549 lung adenocarcinoma cells were used to analyze the expression and secretion of various pro-inflammatory immune response genes. The MED15KO cells displayed downregulated expression of the immune genes CXCL3, CXCL5, and PTGS2, and the immune receptor TLR4, indicated by qPCR. Decreased expression of the pro-inflammatory modulator COX2 (the product of PTGS2) was also observed using immunoblot analysis and decreased secretion of CXCL chemokines and PGE2 (the proinflammatory mediator synthesized by COX2) was observed using ELISA and multiplex assays. The functional effects resulting from this lower expression/secretion of pro-inflammatory mediators were examined, specifically the migration of immune cells towards the cancer cells. A decrease in the migration of THP-1 differentiated macrophages was observed towards the MED15KO cells in comparison to WT A549 cells, using a transwell migration assay. To determine how MED15 regulates the expression/secretion of these pro-inflammatory genes a Cut&Run protocol was optimized. This will reveal if MED15 binds chromatin near TFs known to regulate these immune genes, identifying candidate TFs that may cooperate with MED15. In sum, this data suggests that MED15 is required for the expression and secretion of these immune genes and their ligands, while highlighting an important role for MED15 in pro-inflammatory immune responses in cancer. Citation Format: Sara Cristiano, Xuanjin Cheng, Stefan Taubert. Defining the role of transcriptional coregulator MED15 in immune adaptation in cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6167.