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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

Cancer Research Center, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), Doha 34110, Qatar
College of Health & Life Sciences, Hamad Bin Khalifa University, Qatar Foundation, Doha 34110, Qatar
Institute of Cancer Sciences, University of Manchester, Manchester M20 4GJ, UK
Author to whom correspondence should be addressed.
Vaccines 2019, 7(4), 149;
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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