The functional role of human CD91 SNPs (in cancer) 4095

Description CD91 is a signaling and endocytic receptor expressed on antigen presenting cells (APC) and is essential for effective cancer immunosurveillance. It binds many ligands among which are four heat shock protein (HSP) chaperones. HSP binding to CD91leads to antigen capture and APC maturation allowing the APC to prime T cells and activate NK cells. CD91 is comprised of 4544 amino acids, with nearly 40,000 reported single nucleotide polymorphisms (SNP) in the human population. These SNPs are not well studied in the context of cancer, despite a critical role for CD91 in cancer immunosurveillance, and the impact of CD91 SNPs throughout cancer growth is unknown. Here, we have selected SNPs that appear in a cohort of sarcoma patients that result in missense mutations in CD91. Patient data and protein folding algorithms suggest that several SNPs may have functional consequences on cancer progression, thus we have devised an in vitro based system to look specifically at these SNPs. We are using CRISPR and base editing technology to introduce individual SNPs in CD91 in model systems, including THP1 monocyte cells. These mutants will then be examined for expression of CD91, binding and internalization of HSPs, and expression of cytokines and costimulatory molecules. Further studies will examine CD91 SNPs in mice and humans.