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Breast Cancer Cells and PD-1/PD-L1 Blockade Upregulate the Expression of PD-1, CTLA-4, TIM-3 and LAG-3 Immune Checkpoints in CD4+ T Cells

1
Cancer Research Center, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), Doha 34110, Qatar
2
College of Health & Life Sciences, Hamad Bin Khalifa University, Qatar Foundation, Doha 34110, Qatar
3
Institute of Cancer Sciences, University of Manchester, Manchester M20 4GJ, UK
*
Author to whom correspondence should be addressed.
Vaccines 2019, 7(4), 149; https://doi.org/10.3390/vaccines7040149
Received: 19 September 2019 / Revised: 9 October 2019 / Accepted: 10 October 2019 / Published: 12 October 2019
(This article belongs to the Section Cancer Vaccines and Immunotheraphy)
: Triple negative breast cancer (TNBC) is the most aggressive breast cancer subtype, and it exhibits resistance to common breast cancer therapies. Immune checkpoint inhibitors (ICIs) targeting programmed cell death 1 (PD-1) and its ligand, PD-L1, have been approved to treat various cancers. However, the therapeutic efficacy of targeting PD-1/PD-L1 axis in breast cancer is under clinical investigation. In addition, the mechanisms of action of drugs targeting PD-1 and PD-L1 have not been fully elucidated. In this study, we investigated the effect of human TNBC cell lines, MDA-MB-231 and MDA-MB-468, and the non-TNBC cell line, MCF-7, on the expression of immune checkpoints (ICs) on CD4+ T cell subsets, including regulatory T cells (Tregs), using a co-culture system. We also examined the effect of blocking PD-1 or PD-L1 separately and in combination on IC expression by CD4+ T cell subsets. We found that breast cancer cells upregulate the expression of ICs including PD-1, cytotoxic T lymphocyte-associated antigen-4 (CTLA-4), T cell immunoglobulin and mucin domain-containing protein 3 (TIM-3) and lymphocyte activation gene-3 (LAG-3) in CD4+ T cell subsets. We also found that the co-blockade of PD-1 and PD-L1 further upregulates the co-expression of TIM-3 and LAG-3 on CD4+CD25+ T cells and CD4+CD25+FoxP3+Helios+ Tregs in the presence of TNBC cells, but not in non-TNBC cells. Our results indicate the emergence of compensatory inhibitory mechanisms, most likely mediated by Tregs and activated non-Tregs, which could lead to the development of TNBC resistance against PD-1/PD-L1 blockade.
Keywords: breast cancer; anti-PD-1; anti-PD-L1; Tregs; immune checkpoints breast cancer; anti-PD-1; anti-PD-L1; Tregs; immune checkpoints
MDPI and ACS Style

Saleh, R.; Toor, S.M.; Khalaf, S.; Elkord, E. Breast Cancer Cells and PD-1/PD-L1 Blockade Upregulate the Expression of PD-1, CTLA-4, TIM-3 and LAG-3 Immune Checkpoints in CD4+ T Cells. Vaccines 2019, 7, 149.

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