Immune gene expression profiling reveals heterogeneity in luminal breast tumors

Abstract

BackgroundHeterogeneity of immune gene expression patterns of luminal breast cancer (BC), which is clinically heterogeneous and overall considered as low immunogenic, has not been well studied especially in non-European populations. Here, we aimed at characterizing the immune gene expression profile of luminal BC in an Asian population and associating it with patient characteristics and tumor genomic features.MethodsWe performed immune gene expression profiling of tumor and adjacent normal tissue in 92 luminal BC patients from Hong Kong using RNA-sequencing data and used unsupervised consensus clustering to stratify tumors. We then used luminal patients from The Cancer Genome Atlas (TCGA, N = 564) and a Korean breast cancer study (KBC, N = 112) as replication datasets.ResultsBased on the expression of 130 immune-related genes, luminal tumors were stratified into three distinct immune subtypes. Tumors in one subtype showed higher level of tumor-infiltrating lymphocytes (TILs), characterized by T cell gene activation, higher expression of immune checkpoint genes, higher nonsynonymous mutation burden, and higher APOBEC-signature mutations, compared with other luminal tumors. The high-TIL subtype was also associated with lower ESR1/ESR2 expression ratio and increasing body mass index. The comparison of the immune profile in tumor and matched normal tissue suggested a tumor-derived activation of specific immune responses, which was only seen in high-TIL patients. Tumors in a second subtype were characterized by increased expression of interferon-stimulated genes and enrichment for TP53 somatic mutations. The presence of three immune subtypes within luminal BC was replicated in TCGA and KBC, although the pattern was more similar in Asian populations. The germline APOBEC3B deletion polymorphism, which is prevalent in East Asian populations and was previously linked to immune activation, was not associated with immune subtypes in our study. This result does not support the hypothesis that the germline APOBEC3B deletion polymorphism is the driving force for immune activation in breast tumors in Asian populations.ConclusionOur findings suggest that immune gene expression and associated genomic features could be useful to further stratify luminal BC beyond the current luminal A/B classification and a subset of luminal BC patients may benefit from checkpoint immunotherapy, at least in Asian populations.

Luminal Breast Cancer: Risk of Recurrence and Tumor-Associated Immune Suppression

“…It is evident that the BC-TME is different within the various subtypes, due to their marked heterogeneity. Furthermore, luminal BC was classified into three subgroups, beyond Luminal A and Luminal B subtypes, using the expression of 130 immune-related genes: high-TIL, low-TIL, and high-Interferon Stimulated Genes (ISG) [63]. Thus, we can observe different clinical patterns, prognostic characteristics, and biologic behaviors [63].…”

Genomic Signatures in Luminal Breast Cancer

“…Not much in known about the heterogeneity of immune gene expression patterns of luminal breast cancer since the prognosis of ER-positive breast cancer is less affected by lymphocyte content [27]. However, immune gene expression profiling of luminal tumors identified 3 immune subtypes of luminal breast tumors displaying distinct patterns of immune-related genes (with lower or higher levels of tumor-infiltrating lymphocytes or increased expression of interferon-stimulated genes and enrichment for TP53 somatic mutations) [28]. In addition, luminal A and B carcinomas consist of a mixture of different genotypes and can be further divided into 2 subgroups (diploid/CIN– and aneuploid/CIN+) based on DNA ploidy and chromosomal instability (CIN) [29, 30].…”

Prognostic Significance of Tumor-infiltrating Lymphocytes in Premenopausal, Luminal Breast Cancer Treated with Adjuvant Endocrine Therapy

“…Brie y, the percentage of all mononuclear cells (including lymphocytes and plasma cells) in the stromal compartment within the border of the invasive tumor was visually evaluated. We also developed a supervised machine-learning algorithm for the unbiased detection of TILs based on cell contexture, size and shape within well-de ned regions of the stroma (12).…”

“…Unlike TNBC and HER2 + breast cancers, which are highly proliferating breast cancer subtypes with increased level of tumor mutational burden and genomic instability, luminal breast cancer (LBC) is in general considered as low immunogenic with low rate of lymphocyte-predominant breast cancer (LPBC, TILs ≥ 50%) (10,11). However, given LBC makes up over 70% of all breast cancer patients and a subset of LBC demonstrate a high-TIL phenotype (12), capturing this subgroup of high-TIL tumors and identifying potentially immune-related prognostic markers could have great clinical signi cance (13). However, studies on the potential clinical relevance of TILs in LBC have generated mixed results.…”