Background: Black women suffer 40% higher mortality from breast cancer (BC) compared to non-Hispanic white women, and the underlying causes of these disparities remain uncertain. Growing evidence supports the importance of the immune microenvironment in BC survival, but immune response differences by race are poorly understood. We sought to characterize the immune microenvironment of BC to evaluate how phenotypes of immune response vary across race and tumor intrinsic subtype to impact clinical outcomes. Methods: We leveraged the Carolina Breast Cancer Study (CBCS), a large population-based study that oversampled young (≤50) and black women with invasive breast cancer and collected tumor tissue on >95% of participants. We curated a 48-gene panel representative of 13 individual immune cell types, and performed NanoString gene expression profiling on tissue from 1957 BC patients, including 1033 (53%) Black and 924 (47%) Non-Black women. Consensus clustering was used to identify phenotypes of immune response, and individual immune cell scores were calculated as the median expression of cell-type markers. Immune phenotypes and cell-type scores were compared against validated protein markers and H&E-based quantification of TILs from corresponding tissue microarrays (TMAs). We estimated associations of immune classes with BC intrinsic subtype, ROR-PT scores (calculated as low, medium and high), age and race using relative frequency differences (RFDs), adjusting for age and tumor stage. Cell type scores were compared by race using Welch’s t-tests and adjusted for multiple comparisons with the Benjamani-Hochberg procedure. Results: We identified three BC immune phenotypes primarily defined by features related to an Adaptive-enriched, Innate-enriched, or a Quiet immune microenvironment. These expression-based groups correlated with histological evidence of immune cells from corresponding TMAs. Similarly, expression-based cell scores correlated strongly with protein-based quantification of immune cells from corresponding TMAs (e.g. B-cell score vs. CD19 immunofluorescence, rho=0.75; ICOS RNA counts vs. protein; Rho=0.76). Both Adaptive-enriched and Innate-enriched tumors were associated with high ROR-PT scores [RFD for Adaptive-enriched vs. Quiet: 24.1% (95% CI 19.3-28.8); Innate-enriched vs. Quiet RFD: 13.1 (95% CI 9.1-17); frequencies: 37.2%, 26.2% and 10% for Adaptive, Innate and Quiet, respectively], the basal-like intrinsic subtype [RFD for Adaptive-enriched vs. Quiet: 19.4% (95% CI 14.3-24.6); Innate-enriched vs. Quiet RFD: 9.8 (95% CI 5.6-14.1); frequencies: 43.4%, 27.4% and 8.9% respectively] and Black race [RFD for Adaptive-enriched vs. Quiet: 16.1% (95% CI 10.3-21.9); Innate-enriched vs. Quiet RFD: 9.5 (95% CI 3.9-15); frequencies 60.5%, 53.5% and 42.5% respectively]. After adjusting for tumor subtype, the Adaptive-enriched class remained associated with Black race (RFD for Adaptive-Enriched vs Quiet: 7.5% (95% CI 1.4-13.6). Conversely, tumors in the immune-quiet group were primarily non-basal (90%) with low ROR-PT scores (86.7%). Within the Adaptive-enriched class, Black women displayed decreased CD8 T cell scores (p=0.05) but increased T-reg cell scores (p=0.02) relative to Non-Black women. Conclusion: Immune response appears to be intricately related to race and tumor subtype, with black women having strong associations with adaptive-enriched and innate-enriched immune microenvironments. Differences in CD8 T cell and Treg expression suggest that even within broad classes of immune response, racial differences in specific cell-type distributions exist. Immune response differences may be targetable to improve treatment response, and therefore it is important to identify race- and subtype-specific differences in immune microenvironments.
Citation Format: Alina M Hamilton, Linnea T Olsson, Benjamin C Calhoun, Katherine A Hoadley, Melissa A Troester. Racial differences in breast cancer immune microenvironments [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr SS1-05.