Leveraging outbred mice to identify genetic predictors of durable response to anti-tumor antibody

Abstract

Abstract Trastuzumab is one of many monoclonal antibody (mAb) therapies targeting tumor-associated antigens (TAA) that have markedly improved cancer outcomes. Trastuzumab targets epidermal growth factor 2 (HER2). While it has long been considered the standard-of-care for HER2+ breast cancer treatment, differential response between patients suggests that host genetic background may contribute to an effective response to therapy. We utilize genetically heterogeneous Diversity Outbred (DO) mice to identify genetic elements that influence host response to TAA-mAb therapy. In a cohort of (DOxBALB/c)F1 mice bearing established BALB/c-syngeneic Neu+ (a HER2 homolog) TUBO mammary tumors, we find a divergent response to αNeu mAb therapy (clone 7.16.4). Several phenotypes were collected to compare immunological function to projected tumor doubling time (TDT). These include activation of peripheral anti-tumor T cells and IgG, natural killer cell ADCC competence, bone marrow derived macrophage ADCP/trogocytosis efficacy, and tumor immune cell infiltrate proportions. Contrary to the prospective mechanism of action of trastuzumab, we show that neither capacity for ADCC or ADCP correlate with a robust response to therapy. Following genetic linkage analysis, we identify a locus on Chr 10 that associates with TDT. To verify this locus, we use recombinant inbred collaborative cross (CC) mouse strains (CCxBALB/c) F1 mice that contain or lack this driver genotype. We find pooled survivorship between prospective responder/non-responder strains 2 months post tumor implantation differs by ~8%. This locus alone can’t fully account for a durable response to mAb therapy highlighting the multigenic nature of host immune response.