Abstract P4-06-05: PanCancer profiling reveals population difference in breast cancer immune microenvironment
Authors: Elkhanany A , Takabe K , Khoury T , Omilian A , Cheng D , Katsuta E , Davis W , Yan L , Hong C-C , Bandera E , Ambrosone C , Yao S 
Published: May 2019

Abstract
BACKGROUND. Breast Cancer (BC) outcome in patients (pts) of African ancestry (AA) is worse than pts of European ancestry (EA) despite accounting for socioeconomic status and access. AA have higher hormone receptor negative (HR-) and Triple Negative (TNBC) tumors, subtypes associated with stronger presence of tumor infiltrating lymphocytes (TILs). We hypothesize that BC Immune Microenvironment (IME) composition differs by ancestry, and describe IME from two independent datasets.
METHODS. Transcriptome data from the Cancer Genome Atlas (TCGA) (Group 1, Gp1) were used to estimate 22 IME cell types in BC samples by CIBERSORT. Clinical and overall survival (OS) data were accessed from XENA. Gp2 tissue samples were obtained from Women's Circle of Health study and Pathology Resource Network at Roswell Park Comprehensive Cancer Center and processed using NanoString™ PanCancer Immune Profiling panel, consisting of 770 immunity-related genes describing 24 IME cell types. Immune Dysfunction and Exclusion (TIDE) scores were derived from an algorithm by Jiang et al.
RESULTS. Gp1 consisted of 183 AA and 752 EA, with median age older in EA (54.5 vs 59). On CIBERSORT IME analysis by race, AA had higher IME infiltrates including macrophages (Mp), dendritic cells (DC) and TILs; notably T regulatory (Treg) and T Follicular Helper (Tfh) cells. The ratios of Tregs and Tfh to total TILs were also elevated. When stratified by subtypes, AAs with TNBC/Basal-like BC had higher Tregs and Tfh cells. CD8+ cells were higher in HR+ and high-grade AA pts only. CD4+/total T-cells was higher in AA across all subtypes, and predicted worse OS (HR 3.15[1.07-9.2]). Gp2 had 190 AA and 177 EA with comparable median age at diagnosis (53 versus 54) and tumor grade. By subtype, TNBC had significantly higher total TILs, CD45+, CD8+, exhausted CD8+, Treg, cytotoxic T cells, B, natural killer (NK), activated NK, DC and Mp; yet significantly lower mast cells and neutrophils (p &lt;0.01). CD8+/Exhausted CD8+ and CD8+/Treg ratios were lower in TNBC and higher-grade tumors, and lowest in HR- grade III. Most of immune pathways were enriched in HR- tumors, with only exception being cell cycle genes being remarkably enriched in HR+ tissues (p &lt;0.01). TIDE demonstrated high immune dysfunction in HR- and high exclusion in HR+ tumors. When compared to EA, AA had more TILs, including B, cytotoxic T-cells, exhausted CD8+, NK, activated NK and Tregs (p &lt;0.01). Neutrophils, Mp and CD8+ were higher in EA. EA also had significantly higher ratio of immune cell types to total TILs across cytotoxic, exhausted CD8+ and Tregs, as well as persistent higher neutrophils, Mp and CD8+ ratios. CD8+/Treg ratio was higher in EA. Consistent with Gp1; CD4+/total T-cell ratio was higher in AA across all subtypes.
CONCLUSION. IME differed significantly by HR, grade and ancestry. Aggressive BC demonstrated stronger overall immune response but dysfunctional IME phenotype (higher Treg, lower granulocytes and mast cells ratios). AA had more TILs across all subtypes, but lower ratios of activator (CD8+, Cytotoxic) to suppressor TILs (Treg, exhausted CD8+), demonstrating immune tolerance and immune-desert model, exception being persistently high fraction of CD4+ ratio predicting worse OS.
Citation Format: Elkhanany A, Takabe K, Khoury T, Omilian A, Cheng D, Katsuta E, Davis W, Yan L, Hong C-C, Bandera E, Ambrosone C, Yao S. PanCancer profiling reveals population difference in breast cancer immune microenvironment [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P4-06-05.