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

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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.

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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

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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.

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Authors and Affiliations

  1. Department of Basic Oncology, Hacettepe University Cancer Institute, 06100, Sihhiye, Ankara, Turkey

    Pinar Karasar & Gunes Esendagli

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  1. Pinar Karasar
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  2. Gunes Esendagli
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Correspondence to Gunes Esendagli.

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Karasar, P., Esendagli, G. T helper responses are maintained by basal-like breast cancer cells and confer to immune modulation via upregulation of PD-1 ligands. Breast Cancer Res Treat 145, 605–614 (2014). https://doi.org/10.1007/s10549-014-2984-9

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  • DOI: https://doi.org/10.1007/s10549-014-2984-9

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