Abstract. Breast cancer rates in American women of African ancestry (AA) continue to rise and the gap in
mortality between AAs and women of European ancestry (EA) persists, the reasons for which are largely
unknown. Investigating the hypothesis that evolutionary adaptation to endemic infectious diseases in Africa,
such as malaria, resulted in more robust immune responses, but potentially more aggressive breast cancers
with poorer prognoses, we found striking ancestral differences in distributions of SNPs in immune pathways,
and in circulating cytokines and systemic immune response. Extending our research to local immune response
in the tumor microenvironment (TME), we found a stronger presence of tumor infiltrating lymphocytes (TILs) in
breast tumors from AAs than in EAs. Because TILs are typically associated with better survival, but AAs have
poorer prognosis, in a pilot study, we investigated if various immune cell subtypes in tumor tissues differed in
EAs and AAs. We found an important shift in gene expression profiles for TIL composition and the balance of
immune responses, including a higher ratio of exhausted CD8 to total CD8 T cells in AAs, which was an
independent prognostic factor in survival analysis. These preliminary findings have led us to hypothesize that
the robust nature of the immune response in AAs is important for reshaping the biology of breast tumors,
ultimately leading to the emergence of a more immune-resistant or refractory malignant phenotype. To address
our hypotheses, we will take a multi-pronged approach built upon the established Women’s Circle of Health
Study (WCHS) to resume enrollment of EA cases and continue recruitment of AAs, so that we will have ample
statistical power to compare and investigate immune profiles in tumors from AA and EA women. We will first
profile and compare breast TMEs using transcriptomic profiling in 250 AA vs. 250 EA patients, followed by
validation of top markers and spatial characterization using Vectra multiplex immunofluorescence assay in
tumors from 1,500 AA vs. 716 EA patients, with consideration of other molecular characteristics that differ
between groups. We will examine relationships between immune phenotypes and breast cancer survival, as
well as inflammation-related epidemiologic and social factors that may vary between EAs and AAs, or are
differentially associated with risk by ER status, to investigate why breast tumor immune response would differ
by race. To complement this research, we will employ comprehensive phenotypic and functional assays to
determine the inherent response of immune cells from AA vs. EA cancer patients relative to healthy controls.
Our study will provide evidence at both immune marker and functional levels that breast tumors from AA
women have a stronger immune cell repertoire, but the balance of their TME is shifted towards an unfavorable
dysfunctional state. Our findings may inform clinical investigations of immunotherapy focusing on breast cancer
in AA women, and may guide the way for immunotherapy to activate exhausted T cells, ensuring that all
groups of patients will receive equal benefits from cancer immunotherapy.
