Functional genomics in Diversity Outbred mice identifies Hmgb2 as a candidate regulator of immune checkpoint inhibitor response in melanoma 4592

Abstract Description Our prior studies show that host genetics play a role in response to cancer immunotherapy treatment. Diversity Outbred mice crossed with C57BL/6 mice (DOxB6F1) were inoculated with B16 melanoma and treated with immune checkpoint inhibitors (ICI) anti-PD-1 and anti-CTLA-4. These genetically heterogeneous mice showed differential responses to ICI as measured by tumor growth. Genetic linkage analysis showed that a locus on chromosome 8 (Chr8) was associated with response to ICI treatment. Validation and causal gene identification were conducted in Collaborative Cross (CC) mouse models that were selected based on Chr8 locus genetics to represent predicted ICI responder (ICI R) and non-responder (ICI NR) mice. RNA sequencing (RNAseq) revealed Hmgb2 to be the most highly expressed gene in this locus and that its expression was highest in CD8+ T cells. A recent study identified Hmgb2 as a regulator of T cell exhaustion. Bulk RNAseq of tumor infiltrating CD8+ T cells revealed an inverse correlation between Hmgb2 expression in CD8+ T cells and tumor volume in ICI treated ICI R mice. We crossed ICI R and ICI NR mouse strains with the T cell transgenic OT-I strain to analyze T cell exhaustion post-SIINFEKL peptide exposure. T cell exhaustion phenotypes in vivo in ICI R and ICI NR models will also be measured. These findings show the influence of host genetics on response to ICI treatment and aim to define the role of Hmgb2 in the function of CD8+ T cell-mediated tumor immunity. Funding Sources Supported by R37 CA220482, U-Can-Cer Vive Foundation, Pardee Foundation, DMC Foundation, T32 CA009531. Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)