Abstract P2-10-03: Detrimental impact of T-regulatory cells on outcome of breast cancer in African American population
Authors: Elkhanany Ahmed , Katsuta Eriko , Takabe Kazuaki 
Published: March 2020

BACKGROUND. Outcome of breast cancer (BC) in African American females (AA) remains worse than Caucasian females (CA) after accounting for socioeconomic factors and tumor characteristics. Heterogeneity of tumor immune microenvironment (TIME) composition demonstrated varying roles of infiltrating lymphocytes (TILs) in tumor progression and clinical outcome. We hypothesize that different racial TILs composition impacts downstream tumor signaling and worsens AA BC outcome.

METHODS. The Cancer Genome Atlas (TCGA) harmonized RNA-Seq HTSeq and 450K Methylation data were accessed from GDC. Clinical and CIBERSORT immune composition data downloaded from final PANCAN publications. Outcome data included overall survival (OS), disease specific survival (DSS) and disease free interval (DFI). Differential expression and gene set enrichment analysis (GSEA) were performed using R packages limma and ClusterProfiler. FDR corrected p values &lt; 0.05 were considered significant.

RESULTS. Of 182 AA and 755 CA, TNBC and Basal subtypes were higher in AA (33% and 34% vs 14% and 13% respectively). OS, DSS, DFI and PFI were worse in AA but did not reach significance. Within TNBC, OS of AA was worse than CA (HR 2.18[1.04-4.56]). Compared to CA, AA had higher TILs, T-Regulatory (Tregs) and T-Follicular Helper cells but lower M2 Macrophages (all p&lt;0.01). Within all IHC subtypes, as well as Basal and LumA PAM50 subtypes, Tregs and Treg:TILs ratios were higher in AA (all p&lt;0.05). TILs predicted favorable OS in CA only (HR 0.11[0.27-0.46] versus 1.26[0.87-18]). Treg, Treg:TILs and Treg:CD8+ ratio predicted worse DSS (HR 1525[1-5e7], 51[1.8-1.4e3], 1.05[1-1.1]) and worse DFI (HR 3241[1.14-9e6], 49[1.78-1.3e3], 1.04[1-1.09]) respectively. On GSEA of differentially expressed genes, multiple pathways were enriched in AA including KEGG (IL-17 signaling), MySigDB Hallmarks [H] (IFN-α and IFN-γ), MySigDB Gene Ontology [C5-BP] (CCR Binding), MySigDB Immunological Signatures [C7] (induced Treg signaling) and REACTOME (IL-10 signaling, NF-kB). Notable CA enriched pathways included KEGG (PI3K-Akt, TGF-β, cGMP-PKG) and MySigDB Hallmarks [H] (Hedgehog, early and late Estrogen responses). T-cell exhaustion markers were higher in AA transcriptome, with higher PDCD1, CTLA4, IDO1 and LAG3 but lower TIM3 expression. After correcting for false discovery, AA had lower mean CpG β-value methylation signature of CTLA4, IDO1 and PDCD1.

CONCLUSION. AA had overall more immune infiltrates and different composition of BC TIME compared to CA, with higher immunosuppressive fractions. Tregs were persistently higher across all IHC subtypes, predicted worse outcome and generated higher T-cell exhaustion signature, as well as downstream Treg-specific enriched chemotaxis and activation gene sets in AA compared to CA. These data support the hypothesis of adverse TIME in AA and opens venues of personalized TIME modulation.

Citation Format: Ahmed Elkhanany, Eriko Katsuta, Kazuaki Takabe. Detrimental impact of T-regulatory cells on outcome of breast cancer in African American population [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P2-10-03.