PROJECT SUMMARY/ABSTRACT For multiple subtypes of breast cancer, Black patients endure poorer outcomes than White patients. There are many contributing factors, including socioeconomic inequality, stage at diagnosis, and access to quality care. In addition, there may be biologic, genetic drivers that disproportionally affect Black patients. Black patients with HER2+ breast cancer have lower response rates and experience higher off-target toxicities than their white counterparts, even when stage and age at diagnosis are considered. Trastuzumab is a monoclonal antibody (mAb) designed to bind the HER2 receptor and block growth factor signaling, and the mAb Fc region is also able to engage innate effector immune cells through Fc receptors. Due to this immune involvement, trastuzumab and similar TAA-binding mAbs are classified as targeted immunotherapies (ITx). Importantly, patients who develop endogenous anti-tumor immunity after targeted ITx have a predilection for improved long-term benefit, but it remains unclear what mechanisms regulate durable response. Our preliminary data in a novel genetically diverse mouse model support the hypothesis that host genetic background influences endogenous immune priming after anti-HER2/neu targeted ITx. Importantly, in our model all mice receive genetically identical tumors, which controls for tumor heterogeneity. Genetic linkage analysis in these mice pinpoints specific genomic loci that are associated with treatment outcomes. The leading candidate locus was validated, and mechanistic studies identified differences in the efficiency of macrophages to conduct antibody-dependent phagocytosis (ADCP). These results suggest that host genetics, and potentially genetic ancestry, may regulate the method by which macrophages engulf, process, and/or present tumor antigens to T cells. ADCP and other genetically-regulated immune mechanisms may contribute to the biologic underpinnings of healthcare disparities in immuno-oncology. We have assembled a team of population scientists and tumor immunologists to investigate this hypothesis using patient samples collected in Detroit. We will utilize cutting-edge spatial transcriptomics and imaging mass cytometry technologies to characterize the immune landscape in 184 HER2+ breast cancer tumor sections from patients (~50:50 Black:White) exhibiting response to or recurrence after trastuzumab neoadjuvant therapy. Aim 1 will evaluate immune infiltration patterns, which will be compared by race and association with therapeutic outcomes. In Aim 2, single nucleotide polymorphisms (SNPs) associated with known immune genes and novel candidate genes identified in our preclinical model will also be probed for correlation with trastuzumab response, by race. Collectively, we strive to unveil biologic contributors to healthcare disparities in immuno-oncology, and identify novel actionable genes/pathways to improve targeted ITx outcomes, in addition to key biomarkers to guide clinical decision-m...