Immunological consequences of CD91 Single Nucleotide Polymorphisms in patients with sarcomas

Abstract

Abstract Tumor immunosurveillance is critically dependent on several immune cell types and proteins including CD91. CD91 is expressed on the surface of antigen presenting cells (APCs) and binds a select few heat shock proteins (HSPs) released by dying tumor cells. These HSPs carry tumor antigens and initiate anti-tumor immune responses in de novotumors. We have previously shown among multiple sarcoma types, osteosarcomas are poorly infiltrated by T cells and poorly immune edited. This correlates with reduced expression of CD91 on the surface of intratumoral APCs. CD91 is a highly polymorphic gene within the human population. Over 3500 single nucleotide polymorphisms (SNPs) have been identified, despite the relatively high conservation of CD91 throughout evolution. We have identified 155 of these SNPs within our sarcoma patient population, 11 of which are exonic and non-synonymous. We analyzed the immunologic data we obtained from patients with non-synonymous SNPs to patients with normal CD91 protein sequences. In addition, we used the computational modeling programs SIFT and PolyPhen-2 to predict the effects of these mutations on CD91 protein folding. SNPs rs746886209 and rs758644665 were indicated by both SIFT and PolyPhen-2 to have deleterious effects on CD91 folding and patients with these mutations had below average immune infiltration. While these data are currently correlative, we have developed an in vitromodel to obtain proof of concept.