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Functional heterogeneity of circulating T regulatory cell subsets in breast cancer patients

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Abstract

Background

Regulatory T cells (Tregs) play a major role in tumor escape from immunosurveillance by suppressing effector cells. The number of Tregs is increased in tumor sites and peripheral blood of breast cancer patients. However, the data regarding phenotypic and functional heterogeneity of Treg subpopulations in breast cancer are limited. The present study aimed to investigate the number and suppressive potential of Tregs that possess natural naïve-(N nTregs), effector/memory-like (EM nTregs), and Tr1-like phenotypes in breast cancer patients and healthy women.

Methods

The study included 10 HW and 17 primary breast cancer patients. Numbers of CD4+CD25+FoxP3+CD45RA+ N nTregs, CD4+CD25+FoxP3+CD45RA− EM nTregs, and CD4+IL-4−IL-10+ Tr1 subsets and the expression of CTLA-4, CD39, GITR, LAP, and IL-35 by these Treg subsets were measured in freshly obtained peripheral blood by flow cytometry.

Results

Herein, we demonstrate that the percentages of N nTregs, EM nTregs, CD25+ and FoxP3+ Tr1 cells are elevated in the peripheral blood of breast cancer patients, but do not correlate with cancer stages. Nevertheless, the frequency of CD25+ Tr1 cells was associated with nodal involvement, while the number of EM nTregs correlated with clinical outcome. The expression of CTLA-4 and IL-35 by all assessed Treg subsets was increased throughout all tumor stages (I–III).

Conclusions

Collectively, the current study shows phenotypic alterations in suppressive receptors of Treg subsets, suggesting that breast cancer patients have increased activity of N nTregs, EM nTregs and Tr1 cells; and EM nTregs and CD25+ Tr1 cells represent prospective markers for assessing disease prognosis.

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Abbreviations

CTLA-4:

Cytotoxic T-lymphocyte antigen-4

EM nTregs:

CD4+CD25+FoxP3+CD45RA− effector/memory-like T regulatory cells;

GITR:

Glucocorticoid-induced tumor necrosis factor receptor

iTregs:

Adaptive/induced T regulatory cells

LAP:

Latency associated peptide

nTregs:

Natural T regulatory cells

N nTregs:

CD4+CD25+FoxP3+CD45RA+ naïve-like T regulatory cells

TIL:

Tumor-infiltrating lymphocytes

TNM:

Tumor/node/metastasis classification and staging system

Tr1:

Type 1 T regulatory cells

Tregs:

T regulatory cells

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Acknowledgements

This work was supported by the Grant AP05131691 “Molecular mechanisms of influence of T regulatory cells on tumor cell activity” of Science Committee of Ministry of education and science of the Republic of Kazakhstan.

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Authors and Affiliations

  1. Laboratory of Molecular Immunology and Immunobiotechnology, M.A. Aitkhozhin’s Institute of Molecular Biology and Biochemistry, 86 Dosmuhamedov Str., Almaty, 050012, Kazakhstan

    Yekaterina O. Ostapchuk & Yuliya V. Perfilyeva

  2. Laboratory of Flow Cytometry, Scientific Center for Pediatrics and Children’s Surgery, 146 Al-Farabi Str., Almaty, 050044, Kazakhstan

    Elena A. Kustova & Natalya T. Urazalieva

  3. Mammology Center, Research Institute of Radiology and Oncology, 91 Abay Av., Almaty, 050022, Kazakhstan

    Nazgul A. Omarbaeva & Shynar G. Talaeva

  4. Department of New Technology, Saint-Petersburg Pasteur Institute, 14 Mira Str., Saint-Petersburg, 197101, Russia

    Nikolai N. Belyaev

Authors
  1. Yekaterina O. Ostapchuk
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  2. Yuliya V. Perfilyeva
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  3. Elena A. Kustova
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Correspondence to Yekaterina O. Ostapchuk.

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Ostapchuk, Y.O., Perfilyeva, Y.V., Kustova, E.A. et al. Functional heterogeneity of circulating T regulatory cell subsets in breast cancer patients. Breast Cancer 25, 687–697 (2018). https://doi.org/10.1007/s12282-018-0874-4

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  • DOI: https://doi.org/10.1007/s12282-018-0874-4

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