The characteristics and novel clinical implications of CD4+CXCR5+Foxp3+ follicular regulatory T cells in breast cancer

Xianyuan Miao; Qiusheng Guo; Zhiwen Pan; Xiaohong Xu; Xiying Shao; Xiaojia Wang

doi:10.21037/atm-21-3848

The characteristics and novel clinical implications of CD4+CXCR5+Foxp3+ follicular regulatory T cells in breast cancer

Ann Transl Med. 2021 Aug;9(16):1332. doi: 10.21037/atm-21-3848.

Authors

Xianyuan Miao¹, Qiusheng Guo¹, Zhiwen Pan^{2

3}, Xiaohong Xu^{2

3}, Xiying Shao^{3

4}, Xiaojia Wang^{3

4}

Affiliations

¹ The Second Clinical Medical College of Zhejiang Chinese Medical University, Hangzhou, China.
² Department of Clinical Laboratory, Cancer Hospital of the University of Chinese Academy of Sciences/Zhejiang Cancer Hospital, Hangzhou, China.
³ Institute of Cancer and Basic Medicine (ICBM), Chinese Academy of Sciences, Hangzhou, China.
⁴ Department of Medical Oncology (Breast Cancer), Cancer Hospital of the University of Chinese Academy of Sciences/Zhejiang Cancer Hospital, Hangzhou, China.

Abstract

Background: Follicular regulatory T cells (Tfr) are a subset of regulatory T cells (Tregs) that suppress the humoral immune response in the germinal center. They are associated with increased rates of disease stabilization and decreased autoantibody levels in a variety of tumor and autoimmune diseases. The binding of T-cell immunoglobulin mucin 3 (TIM-3) and its ligand on the surface of Tfr cells could result in the depletion of T lymphocytes and the termination of the immune response mediated by helper T cell 1. However, the role of Tfr cells in breast cancer (BC) remains unclear.

Methods: In this study, we detected the expression of CD4+CXCR5+Foxp3+Tfr cells in the peripheral blood of 35 BC patients and 30 healthy control patients by flow cytometry, and analyzed the relationship between Tfr cells and the clinical characteristics of patients. In addition, the expression of TIM-3 on the surface of Tfr cells in 6 triple-negative BC (TNBC) patients was further investigated using mass spectrometry.

Results: We found a significant increase in Tfr cells in BC patients compared to healthy control patients (23.47%±9.70% vs. 10.99%±4.68%; P=0.001). Notably, the increase was more significant in early stage than advanced stage TNBC patients (28.52%±10.75% vs. 18.69%±5.19%; P=0.006), and there was a negative correlation between Tfr cells and serum lactate dehydrogenase (LDH) in early stage TNBC patients (r=-0.585; P=0.008). Additionally, we found that the expression of Tfr cells was higher in TNBC patients than luminal BC patients (28.25%±10.11% vs. 18.5%±8.15%; P=0.028); however, there was no significant difference in expression in hormone receptor positive (HR+) BC and hormone receptor negative (HR-) BC (P=0.141) patients. Notably, the surface of Tfr cells of TNBC patients had higher levels of TIM-3 expression than those of healthy control patients (3.93±0.92 vs. 2.65±0.15, respectively; t=-3.02; P<0.05), which the mass spectrometry showed were positively correlated with the intracellular Foxp3 expression of Tfr cells (r=0.82; P=0.036).

Conclusions: Our results suggest that circulating Tfr cells and the expression of TIM-3 were significantly increased in BC patients, which were related to stage and histological type, and may be involved in the pathogenesis of BC.

Keywords: Breast cancer (BC); T-cell immunoglobulin mucin 3 (TIM-3); follicular regulatory T cell (Tfr).