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Background Immunogenic cell death (ICD) stimulates the immune system to produce an anti-tumor immune response, essential for immunotherapy and overall survival. In this work, we utilized a novel murine model of breast cancer to identify an ICD gene signature, and correlated ICD-related genes with cancer outcomes, immune response, and genomic variation. This novel mouse model of breast cancer was developed to replicate human heterogeneity.Methods The FVB C3(1)-T-antigen (‘C3Tag’) mouse develops spontaneous tumors in the mammary glands of female mice and is well established to resemble human basal-like triple negative breast cancer (TNBC). TNBC is an aggressive subtype with few clinical approaches and poor patient outcomes. Thus, to model human heterogeneity in BC outcomes, we systematically crossed the C3Tag GEMM into the BXD recombinant inbred family – the largest and best characterized genetic reference population. 1 The new model is termed ‘BXD-BC’ and F1 hybrids of the cross have isogenic genomes that are reproducible. BXD-BCs are a potent tool to determine the impact of genetic modifiers on BC tumor traits. Using N=29 BXD-BC strains, we demonstrated significant heritable variations in the severity of TNBC characteristics such as tumor latency, multiplicity, and survival. RNAseq was performed on tumors from each strain.Results BXD-BC tumor latency is positively correlated to an established ICD-gene signature. 2 We then generated an ICD gene score that significantly correlated to tumor latency in our mouse model. Using systems genetics, the ICD gene score mapped to a putative quantitative trait locus on chromosome 6, which significantly regulated the gene expression of vacuolar-ATPase proton pumps across various immune cells.Conclusions This work extends the findings of ICD gene signatures in patient data sets, to genetic variance and gene expression in the immune cells. Future work will use the BXD-BC model to test the correlation between ICD-related genes and response to immunotherapy.References Ashbrook DG, Arends D, Prins P, Mulligan MK, Roy S, Williams EG, Lutz CM, Valenzuela A, Bohl CJ, Ingels JF, McCarty MS, Centeno AG, Hager R, Auwerx J, Lu L, Williams RW. A platform for experimental precision medicine: the extended BXD mouse family. Cell Syst. 2021;12:235–247Garg AD, De Ruysscher D, Agostinis P. Immunological metagene signatures derived from immunogenic cancer cell death associate with improved survival of patients with lung, breast or ovarian malignancies: a large-scale meta-analysis. Oncoimmunology. 2015;5.