Project Summary This application will address cancer health disparities in Black residents of metropolitan Detroit, specifically evaluating racial differences in genetic regulation of anti-tumor immunity 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. Black women with HER2+ breast cancer have substantially poorer outcomes overall and among those treated with trastuzumab compared to White patients, even after controlling for clinical and sociodemographic factors, suggesting biologic factors may also contribute. Endogenous adaptive immunity may be a requirement for sustained tumor protection after monoclonal antibody treatment, and the role of genetic regulation of immune tolerance, autoimmunity, and tumor immunity is well documented. Further, there is strong evidence for racial differences in both immune pathway genetic variation and the tumor immune microenvironment. A better understanding of the mechanisms regulating response to anti-HER2 antibodies is critical for the development of improved clinical strategies, and the inclusion of a diverse patient population and consideration of group- and individual-level genetic differences is essential for ensuring that these strategies are equitable. We have assembled a strong multidisciplinary team of investigators committed to understanding the biological underpinnings of racial disparities in cancer. The overarching goals of this P20 are (1) to identify ancestry-specific genetic regulators of macrophage function and response to anti-HER2 antibody therapy that potentially underlie racial differences in response to this targeted immunotherapy and (2) to establish a robust infrastructure to support and develop innovative, productive immuno-oncology and health disparities research collaborations. The application comprises one Research Project and an Administrative Core at an NCI- designated comprehensive Cancer Center in Detroit, Michigan, where the majority of census tracts are medically underserved areas based on HRSA definitions. The aims of this P20 are (1) to accelerate translational research to reduce racial disparities in HER2+ breast cancer outcomes by characterizing race-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 intersectional, translational research on immuno-oncology and the biology of cancer health disparities, achieve R01/P01-level funding, and ultimately reduce cancer health disparities in immuno-oncology outcomes. This work will provide the basis for moving towards a more race-inclusive, equity-focused precision medicine approach to the use of immunotherapies to improve overall treatment response, identify novel biomarkers, and reduce racial disparities in outcom...