Abstract C155: Immune profiling reveals distinct ancestry-associated immune surveillance programmes in breast cancer
TL;DR
A large multimodal study integrating clinical, systemic and spatial immune profiling to investigate ethnicity-associated immune surveillance while minimizing socioeconomic confounding demonstrates divergent ancestry-associated alterations in immune surveillance profiles, which likely contributes to mechanisms underpinning inequitable breast cancer outcomes.
Abstract
Black women with breast cancer experience poorer outcomes than White women. It is recognized that an array of factors including ancestry and socioeconomic status, including environmental inequalities, as well as surveillance landscape affect this disparity. However, the specific contribution of genetic ancestry to anti-tumor immunity remains poorly understood. As ancestry, socioeconomic and environmental disadvantage are intertwined, distinguishing immune programmes associated with each factor has been challenging. Focusing on treatment naïve early breast cancer patients, we therefore performed a large multimodal study integrating clinical, systemic and spatial immune profiling to investigate ethnicity-associated immune surveillance while minimizing socioeconomic confounding. Clinical characteristics, whole blood counts, Index of Multiple Deprivation (IMD) were available for 810 breast cancer patients (598 White; 212 Black) and 87 healthy controls. A subset of patients have estimates of genetic ancestry available, complementing self-reported ethnicity. High-dimensional flow cytometry was performed in 155 patients (104 White; 51 Black), high-throughput Olink serum proteomics in 104 patients (63 White; 41 Black), digital pathology in 219 tumor-draining lymph nodes from 88 patients, CD20/CD3 IHC was performed in 211 lymph nodes from 92 patients and 20-plex PhenoCycler imaging in 30 lymph nodes (17 White; 13 Black). To identify immune programmes specifically associated with ancestry, analyses were performed by adjusting for age, stage, subtype and IMD. Independent of these confounders, black patients exhibited reduced neutrophil-to-lymphocyte ratio, inhibitory NK-cell phenotypes, expansion of cDC1s and activated antigen-presenting monocytes, together with a pro-inflammatory chemokine signature. Spatial imaging revealed remodeling of tumor-draining lymph node immune architecture, with reduced GZMB+ CD8+ T cells, altered B-cell zone organization and increased M2-like macrophages in B cell zone of involved lymph nodes. Comprehensive H&E and CD20/CD3 IHC analyses of the full lymph node cohort are ongoing and will provide additional validation of spatial immune alterations identified by high-dimensional imaging. This multimodal study demonstrates differential circulating and lymphoid immune signatures associated specifically with ancestry. While several systemic and lymph node immune programmes persisted after minimizing socioeconomic confounding, others were more associated with deprivation indices and environmental inequalities, indicating complementary influences on immune organization. These findings demonstrate divergent ancestry-associated alterations in immune surveillance profiles, which likely contributes to mechanisms underpinning inequitable breast cancer outcomes. Bryan Boon Han Ng, Paul R. Buckley, Thanussuyah Alaguthurai, Helen Kakkassery, Tara Chait, Katie Broome, Benjamin Nicholls-Mindlin, Sophie Stewart, Rosalind Graham, Ruifang Lu, Esme Carpenter, Melek Akay, Hiu-Yan Lau, Yi-Ting Tsai, Farhana Hossain, Syed Haider, Nigel Mongan, Fieke Froeling, Clayton Yates, Melissa Davis, Patrycja Gazinska, Sheeba Irshad. Immune profiling reveals distinct ancestry-associated immune surveillance programmes in breast cancer [abstract]. In: Proceedings of the 19th AACR Conference on the Science of Cancer Health Disparities; 2026 Oct 18-21; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2026;35(10 Suppl):Abstract nr C155.