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Breast Cancer Research and Treatment

, Volume 145, Issue 3, pp 605–614 | Cite as

T helper responses are maintained by basal-like breast cancer cells and confer to immune modulation via upregulation of PD-1 ligands

Preclinical study

Abstract

A conspicuous T cell infiltration is frequently observed in triple-negative and/or basal-like breast cancers. Since the immunological course of breast cancer is explicitly directed by helper T cells, this study aims to determine the influence of basal-like breast cancer (BLBC) cells on CD4+ T cell responses. Co-cultures were established with breast cancer cell lines and CD4+ T cells under stimulatory conditions. Helper T cell activation, proliferation, cytokine secretion, and differentiation were assessed. Protein and mRNA expression of PD-1 ligands were determined on breast cancer cell lines. Blockade assays were performed in order to determine the functional assets of PD-1 ligation. In contrast to luminal breast cancer cells, BLBC cells allowed CD4+ T cell activation, proliferation, and IFN-γ secretion, but only to a certain extent. A substantial population of CD25+CD127low/− regulatory T (Treg) cells was also induced in BLBC co-cultures. In return, IFN-γ stimulated the upregulation of PD-L1 (B7-H1) and/or PD-L2 (B7-DC) inhibitory molecules on the basal-like cells. In prolonged periods of co-culturing, blockade of PD-1 ligands on BLBC cell lines impaired Treg differentiation, restored IL-2 secretion, and increased CD8+ T cell activation. In conclusion, T helper responses were maintained by BLBC cells. On the other hand, IFN-γ secreted from Th1 and other immune cells upregulated the expression of PD-1 ligands on BLBC cells and modulated the immune reactions. Our results indicate the capacity of BLBCs to adapt to IFN-γ-mediated anti-tumor immune responses and to evade immunity via upregulation of PD-1 ligands.

Keywords

Basal-like breast cancer T lymphocyte Immune modulation PD-1 PD-L1 PD-L2 

Abbreviations

BLBC

Basal-like breast cancer

GITR

Glucocorticoid-induced TNFR-related protein

GM-CSF

Granulocyte macrophage-colony stimulating factor

ICOS

Inducible T cell costimulator

IFN

Interferon

IL

Interleukin

OD

Optical density

PD-1

Programmed death-1

PD-L

Programmed death-ligand

PMA

Phorbol 12-myristate 13-acetate

SD

Standard deviation

Th cell

Helper T cell

Th1 cell

Type-1 helper T cell

TNF

Tumor necrosis factor

Treg cell

Regulatory T cell

Notes

Acknowledgments

This study is funded by Hacettepe University Research Unit (Project no. 013D03104001 and 013D10104001). We thank Gurcan Tunali, MSc and Parisa Sarmadi, MSc for additional support in the conduct of experiments.

Conflict of interests

The authors declared that there are no competing interests.

Supplementary material

10549_2014_2984_MOESM1_ESM.pdf (563 kb)
Supplementary material 1 (PDF 563 kb)

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Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  1. 1.Department of Basic OncologyHacettepe University Cancer InstituteSihhiye, AnkaraTurkey

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