Transcriptional regulation of CD91 expression in antigen presenting cells and its impact on immune responses and disease 2231601

Abstract Introduction Cancer immunosurveillance depends on elimination of emerging tumors by cytotoxic T cells. Priming of T cells relies on the delivery of 3 signals from antigen-presenting cells (APC) in the form of MHC-peptide complexes, co-stimulatory molecules, and cytokines. In cancer cells, tumor peptides are associated with HSPs. Upon release by necrotic cancer cells, HSPs are captured by CD91 and these peptide antigens are cross presented. CD91-mediated signaling networks are also initiated by HSP binding and activates DCs to provide co-stimulation and cytokines. Interestingly, variable CD91 expression levels on APCs in humans correlate with differential cancer outcomes and anti-tumor immune responses. While the functional importance of CD91 in disease is known, the transcriptional control of CD91 in APCs remains unclear and represents a potential mechanism to explain the variable expression. The objective of this work is to utilize in vitro genetic screens to identify factors controlling CD91 expression in APCs. We hypothesize that disruption of these factors will change CD91 expression and regulate CD91-dependent immune functions, including cancer immunosurveillance. Methods To identify transcription factors (TFs) regulating CD91 expression and validate direct transcriptional regulation, we will use an unbiased TF CRISPR screen, ChIP-PCR, select TF siRNA, and CD91-promoter driven luciferase reporter assays. Results We have identified candidate TFs using in silico transcription factor binding prediction analysis and will further screen with siRNA knockdown analysis. Conclusion Ultimately, this work aims to uncover novel transcriptional circuits controlling APC function. Translationally, these findings will inform rational design for dendritic cell-based therapies and identify druggable molecular targets for not only cancer, but also infectious, neurological, cardiovascular, and autoimmune diseases, where CD91 has been shown to play important roles. Funding Source NIH Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)