Genetic linkage analysis of cancer vaccine response in Diversity Outbred mice

Abstract

Recent advances in cancer immunotherapy demonstrate the power of anti-tumor immunity, however only a fraction of patients maintain durable responses. To test the hypothesis that genetic variation determines cancer immunotherapy response, we conducted genetic linkage analysis of HER2 vaccine response in Diversity Outbred (DO) mice. Our HER2 DNA vaccine has shown varying anti-tumor activity in mice, cats and human patients. Differential vaccine response was found in HER2 transgenic (Tg) mice of BALB/c versus C57BL/6 backgrounds. DO mice, produced by non-sibling crossing of 8 mouse stains (A/J, C57BL/6, 129S1/Svlm, NOD, NZO, CAST/EiJ, PWK/PhJ and WSB/EiJ) incorporate >90% of all genetic variation in mice. The fully sequenced founder strain genomes enable genetic linkage analysis using Mouse Universal Genotyping Array (GigaMUGA), which consists of >150,000 genetic markers, mostly single nucleotide variants. DO mice were bred with C57BL/6 HER2 Tg mice, generating HER2 DO mice that express human HER2 as a self-antigen. A wide range of IgG (1.8 – 50 μg/mL) and IFNg producing T cells (0 – 348/10⁶ splenocytes) were detected after 2× vaccination with an adenoviral vaccine encoding human HER2. Genetic loci associated with positive response (p<10⁻⁵) were sought by linear regression analysis. Immune-related genes within identified loci were examined. Preliminary analysis links IgG response to NFkB, IL6, and IFNg-related gene clusters, and IFNg producing T cell response to NFkB, IL6, IL10, Akt and p38 MAPK-related gene clusters. Further analysis will define and rank genetic variants of candidate immune regulators to help identify vaccine responsive individuals.