Disparities in Immuno-oncology Outcomes in Detroit (DIODE)

This application will address breast cancer in high-risk groups among residents of metropolitan Detroit, specifically evaluating differences in genetic regulation of tumor immune response in HER2+ breast cancer as an example of the type of transdisciplinary work that will be catalyzed through the robust grant-planning infrastructure developed in this P20. Many Detroit residents with HER2+ breast cancer belong to high-risk groups with substantially poorer outcomes overall, and among those treated with trastuzumab, even after controlling for clinical and patient-level factors, suggesting biologic factors may also contribute. Endogenous adaptive immunity may be a requirement for sustained tumor protection after monoclonal immune treatment, and the role of genetic regulation of immune tolerance, autoimmunity, and tumor immunity is well documented. Further, there is strong evidence for within-population differences in both immune pathway genetic variation and the tumor immune microenvironment. A better understanding of the mechanisms regulating response to HER2-targeted antibodies is critical for the development of improved clinical strategies, and the inclusion of a genetically heterogeneous patient population and consideration of group- and individual-level genetic differences is essential. The overarching goals of this P20 are (1) to identify ancestry-specific genetic regulators of macrophage function and response to HER2-targeted antibody therapy that potentially underlie differences in response to this targeted immunotherapy and (2) to establish a robust infrastructure to support and develop innovative, productive immuno-oncology and population science research collaborations. The application comprises one Research Project and an Administrative Core at an NCI-designated comprehensive Cancer Center in Detroit, Michigan. The aims of this P20 are (1) to accelerate translational research to reduce high mortality rates among patients with HER2+ breast cancer by characterizing ancestry-specific immune profiles with respect to the tumor environment and host genetic background to determine their contribution to response to treatment with anti-HER2 antibody therapies and (2) to strengthen the existing programmatic structure to facilitate interdisciplinary, translational research in immuno-oncology and population science, achieve R01/P01-level funding, and ultimately improve immuno-oncology outcomes among HER2+ breast cancer patients. This work will provide the basis for moving towards a more precision medicine approach to the use of immunotherapies to improve overall treatment response and identify novel biomarkers.