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
<p dir="ltr">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 trea...
محفوظ في:
| المؤلف الرئيسي: | |
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| مؤلفون آخرون: | , , |
| منشور في: |
2019
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| الموضوعات: | |
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إضافة وسم
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| _version_ | 1864513505631141888 |
|---|---|
| author | Reem Saleh (3513056) |
| author2 | Salman M Toor (9279953) Sarah Khalaf (16555642) Eyad Elkord (5396390) |
| author2_role | author author author |
| author_facet | Reem Saleh (3513056) Salman M Toor (9279953) Sarah Khalaf (16555642) Eyad Elkord (5396390) |
| author_role | author |
| dc.creator.none.fl_str_mv | Reem Saleh (3513056) Salman M Toor (9279953) Sarah Khalaf (16555642) Eyad Elkord (5396390) |
| dc.date.none.fl_str_mv | 2019-10-12T03:00:00Z |
| dc.identifier.none.fl_str_mv | 10.3390/vaccines7040149 |
| dc.relation.none.fl_str_mv | https://figshare.com/articles/journal_contribution/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/27003565 |
| dc.rights.none.fl_str_mv | CC BY 4.0 info:eu-repo/semantics/openAccess |
| dc.subject.none.fl_str_mv | Biomedical and clinical sciences Immunology Oncology and carcinogenesis breast cancer anti-PD-1 anti-PD-L1 Tregs immune checkpoints |
| dc.title.none.fl_str_mv | 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 |
| dc.type.none.fl_str_mv | Text Journal contribution info:eu-repo/semantics/publishedVersion text contribution to journal |
| description | <p dir="ltr">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<sup>+</sup> 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<sup>+</sup> 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<sup>+</sup> 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<sup>+</sup>CD25<sup>+</sup> T cells and CD4<sup>+</sup>CD25<sup>+</sup>FoxP3<sup>+</sup>Helios<sup>+</sup> 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.</p><h2>Other Information</h2><p dir="ltr">Published in: Vaccines<br>License: <a href="https://creativecommons.org/licenses/by/4.0/" target="_blank">https://creativecommons.org/licenses/by/4.0/</a><br>See article on publisher's website: <a href="https://dx.doi.org/10.3390/vaccines7040149" target="_blank">https://dx.doi.org/10.3390/vaccines7040149</a></p> |
| eu_rights_str_mv | openAccess |
| id | Manara2_df304f698056554fbe8d2d6d56f33c90 |
| identifier_str_mv | 10.3390/vaccines7040149 |
| network_acronym_str | Manara2 |
| network_name_str | Manara2 |
| oai_identifier_str | oai:figshare.com:article/27003565 |
| publishDate | 2019 |
| repository.mail.fl_str_mv | |
| repository.name.fl_str_mv | |
| repository_id_str | |
| rights_invalid_str_mv | CC BY 4.0 |
| spelling | 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 CellsReem Saleh (3513056)Salman M Toor (9279953)Sarah Khalaf (16555642)Eyad Elkord (5396390)Biomedical and clinical sciencesImmunologyOncology and carcinogenesisbreast canceranti-PD-1anti-PD-L1Tregsimmune checkpoints<p dir="ltr">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<sup>+</sup> 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<sup>+</sup> 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<sup>+</sup> 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<sup>+</sup>CD25<sup>+</sup> T cells and CD4<sup>+</sup>CD25<sup>+</sup>FoxP3<sup>+</sup>Helios<sup>+</sup> 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.</p><h2>Other Information</h2><p dir="ltr">Published in: Vaccines<br>License: <a href="https://creativecommons.org/licenses/by/4.0/" target="_blank">https://creativecommons.org/licenses/by/4.0/</a><br>See article on publisher's website: <a href="https://dx.doi.org/10.3390/vaccines7040149" target="_blank">https://dx.doi.org/10.3390/vaccines7040149</a></p>2019-10-12T03:00:00ZTextJournal contributioninfo:eu-repo/semantics/publishedVersiontextcontribution to journal10.3390/vaccines7040149https://figshare.com/articles/journal_contribution/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/27003565CC BY 4.0info:eu-repo/semantics/openAccessoai:figshare.com:article/270035652019-10-12T03:00:00Z |
| spellingShingle | 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 Reem Saleh (3513056) Biomedical and clinical sciences Immunology Oncology and carcinogenesis breast cancer anti-PD-1 anti-PD-L1 Tregs immune checkpoints |
| status_str | publishedVersion |
| title | 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 |
| title_full | 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 |
| title_fullStr | 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 |
| title_full_unstemmed | 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 |
| title_short | 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 |
| title_sort | 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 |
| topic | Biomedical and clinical sciences Immunology Oncology and carcinogenesis breast cancer anti-PD-1 anti-PD-L1 Tregs immune checkpoints |