Abstract Disparities in breast cancer survival among ethnic groups have been a persistent finding over the past five decades, exacerbated in part by the lack of improvement to non-white patient outcomes, despite treatment advancements that have improved clinical outcomes in white women. A significant part of this disparity is health equity; however, recent evidence from several groups indicates that histologic and pathologic diversity in tumor phenotypes among ethnic groups is also a key factor affecting the differences in clinical outcome. Specifically, correlated findings among women with significant West African ancestry reveal that there is a genetic link between women across the African Diaspora that is associated with aggressive tumor phenotypes, including triple-negative breast cancer. Aside from the global incidence of TNBC being higher in regions with relatively higher numbers of women with African ancestry, we also find that pathologic progression of tumors in African Americans tends to mimic that of African women. Tumor progression is directly related to the immune response elicited by the onset of tumor growth as well as the underlying tissue microenvironment, particularly the inflammatory status. We have identified several lines of evidence that suggest there is a distinct immune response to breast cancer, which is also tumor phenotype/subtype specific, when comparing patients of significant African ancestry with those of primarily European ancestry. These findings suggest that there could be a unique mechanism of tumor immunology at work, driven by population private genetic alleles derived in Africa and transmitted throughout the African Diaspora, causing a unique tumor phenotype in these breast cancer patients. This unique phenotype is likely the key factor in distinct treatment responses that result in poorer clinical outcomes for African American women. Citation Format: Melissa B. Davis, Brittany D. Jenkins, Rachel A. Martini, Haythem Ali, Clayton C. Yates, Elizabeth A. Howerth, Petros Nikolinakos, Michele Monteil, Lisa A. Newman. Exploring the impact of African ancestry in tumor immune response, a possible role in disparate clinical outcomes [abstract]. In: Proceedings of the Eleventh AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2018 Nov 2-5; New Orleans, LA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl):Abstract nr IA27.