Disparity in Tumor Immune Microenvironment of Breast Cancer and Prognostic Impact: Asian Versus Western Populations

Abstract

Background: The clinicopathological features and prognosis of breast cancer in Asia are different from those in the Western countries. Tumor-infiltrating immune cells can influence the outcome of patients with breast cancer, but they have not been systemically evaluated in Asian patients with breast cancer.

Methods: We compared the immune score, composition, and prognostic impact of infiltrating immune cells between Asian and Western patients with breast cancer by analyzing gene expression profiles from eight Gene Expression Omnibus data sets and The Cancer Genome Atlas data set. The Estimation of Stromal and Immune Cells in Malignant Tumours Using Expression Data (ESTIMATE) and Cell Type Identification by Estimating Relative Subsets of Known RNA Transcripts (CIBERSORT) algorithms were used to determine the immune score and composition of tumor-infiltrating immune cells, respectively.

Findings: This study included 462 Asian patients and 2,186 Western patients. Tumors of Asian patients had significantly higher immune score, particularly in the luminal B and HER2-enriched subtypes. High immune score was associated with favorable prognosis in both Asian and Western patients, and Asian race with a high ESTIMATE immune score provided additional power to predict longer disease-free survival. Activated CD4 T cells and M2 macrophages were the most strongly associated with survival in both Asian and Western patients.

Interpretation: Our study highlights the difference in tumor immune microenvironments between Asian and Western patients. The higher ESTIMATE immune score, which represents more abundant tumor-infiltrating immune cells, in tumors of Asian patients partly explains their favorable prognosis.

Implications for practice: The tumor microenvironment serves as an interface that affects the human body's reaction to cancer cells. Evidence has revealed that tumor-infiltrating immune cells were associated with patient prognosis. This study demonstrated the disparity of tumor microenvironments and their prognostic impact between Asian and Western patients with breast cancer. The differences in immune score partially explained the racial survival differences noted in recent studies. Integrated analysis of tumor cells, tumor microenvironment, and racial effect may significantly improve recurrence risk prediction for patients with stage I-III breast cancer. Because the effect of tumor microenvironment varies across different populations, a model of interaction between immune score and race/ethnicity is recommended in accessing the risk of patients with cancer.

Keywords: Asia; Breast cancer; Composition; Immune cell; Prognosis.

Figure 1

Study flow diagram. By applying searching filter, 177 studies were found. A total of eight data sets met selection criteria in further evaluation. Abbreviations: GEO, Gene Expression Omnibus; TCGA, The Cancer Genome Atlas.

Figure 2

Overall survival by race and Estimation of Stromal and Immune Cells in Malignant Tumours Using Expression Data (ESTIMATE) immune core across all subtypes and individual Prediction Analysis of Microarray 50 (PAM50) subtypes. (A): All subtypes. Asian race and high immune score were associated with longer survival. (B–F): PAM50 subtypes, including luminal A (B), luminal B (C), HER2‐enriched (D), basal (E), and normal‐like (F). The prognostic effects of Asian race and high immune score remained significant in patients with luminal A and basal breast cancer. A similar trend can be seen in luminal B subtype (p = .05). In HER2‐enriched and normal‐like subtypes, the prognostic effects of Asian race and high immune score were insignificant. Abbreviation: IS, immune score.

Figure 3

Proportions of immune cell subsets in Asian and Western breast tumors. Monocytes, M1 macrophages, gamma‐delta T cells, naive CD4 T cells, and regulatory T cells exhibited different percentage between races, but statistical analysis was insignificant. * indicates p value calculated by proportional z test with Benjamini‐Hochberg adjustment. Abbreviation: NK, natural killer.

Figure 4

Prognostic effects of individual immune cell subsets on overall survival. (A): Effects of cell subsets on Asian patients. Adjusted for age, stage, and Prediction Analysis of Microarray 50 (PAM50) subtype, activated CD4 T cells, memory B cells, and CD8 T cells were associated with better prognosis, whereas M2 macrophage was associated with worse prognosis. (B): Effects of cell subsets on Western patients. The effects of activated CD4 T cells, CD8 T cells, and M2 macrophages were similar in Western patients with breast cancer. * indicates p < .05. Abbreviations: CI, confidence interval; NK, natural killer.