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STAT3 Silencing and TLR7/8 Pathway Activation Repolarize and Suppress Myeloid-Derived Suppressor Cells From Breast Cancer Patients

Cancer cells escape immune destruction. From this perspective, myeloid-derived suppressor cells (MDSCs), which are immunosuppressive in various cancers including breast cancer (BC), are significant. However, the precise mechanisms are unknown. We isolated HLA-DR(-)CD33(+) MDSCs and CD3(+) T cells fr...

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Autores principales: Safarzadeh, Elham, Mohammadi, Ali, Mansoori, Behzad, Duijf, Pascal H. G., Hashemzadeh, Shahryar, Khaze, Vahid, Kazemi, Tohid, Derakhshani, Afshin, Silvestris, Nicola, Baradaran, Behzad
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7933669/
https://www.ncbi.nlm.nih.gov/pubmed/33679700
http://dx.doi.org/10.3389/fimmu.2020.613215
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author Safarzadeh, Elham
Mohammadi, Ali
Mansoori, Behzad
Duijf, Pascal H. G.
Hashemzadeh, Shahryar
Khaze, Vahid
Kazemi, Tohid
Derakhshani, Afshin
Silvestris, Nicola
Baradaran, Behzad
author_facet Safarzadeh, Elham
Mohammadi, Ali
Mansoori, Behzad
Duijf, Pascal H. G.
Hashemzadeh, Shahryar
Khaze, Vahid
Kazemi, Tohid
Derakhshani, Afshin
Silvestris, Nicola
Baradaran, Behzad
author_sort Safarzadeh, Elham
collection PubMed
description Cancer cells escape immune destruction. From this perspective, myeloid-derived suppressor cells (MDSCs), which are immunosuppressive in various cancers including breast cancer (BC), are significant. However, the precise mechanisms are unknown. We isolated HLA-DR(-)CD33(+) MDSCs and CD3(+) T cells from BC patients’ peripheral blood and healthy donors through MACS and immunophenotyped by flow cytometry. Transfection of short-interfering RNAs and treatment with a TLR7/8 agonist altered pathway activities in vitro. Gene expression was analyzed using qRT-PCR, western blotting, and immunohistochemistry. Our findings showed an association between the progression of BC and increased levels of circulating HLA-DR(-)CD33(+) MDSCs. These cells strongly suppress both autologous and analogous CD3(+) T cell proliferation and enter the tumor microenvironment. We also identified increased STAT3 signaling and increased IDO and IL-10 expression in BC-derived MDSCs as immunosuppression mechanisms. Further, STAT3 inhibition and TLR7/8 pathway stimulation reduce the immunosuppressive activity of patient-derived MDSCs on T cells by inducing MDSC repolarization and differentiation into mature myeloid cells. This also alters the expression of critical cytokines and transcription factors in CD3(+) T cells and, importantly, reduces breast cancer cells’ proliferation. Finally, while chemotherapy is able to significantly reduce circulating MDSCs’ level in patients with breast cancer, these MDSCs remained highly T cell-suppressive. We identified a novel molecular mechanism of MDSC-mediated immunosuppression. STAT3 inhibition and TLR7/8 pathway stimulation in MDSCs repolarize and suppress MDSCs from breast cancer patients. This offers new opportunities for BC immunotherapy.
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spelling pubmed-79336692021-03-06 STAT3 Silencing and TLR7/8 Pathway Activation Repolarize and Suppress Myeloid-Derived Suppressor Cells From Breast Cancer Patients Safarzadeh, Elham Mohammadi, Ali Mansoori, Behzad Duijf, Pascal H. G. Hashemzadeh, Shahryar Khaze, Vahid Kazemi, Tohid Derakhshani, Afshin Silvestris, Nicola Baradaran, Behzad Front Immunol Immunology Cancer cells escape immune destruction. From this perspective, myeloid-derived suppressor cells (MDSCs), which are immunosuppressive in various cancers including breast cancer (BC), are significant. However, the precise mechanisms are unknown. We isolated HLA-DR(-)CD33(+) MDSCs and CD3(+) T cells from BC patients’ peripheral blood and healthy donors through MACS and immunophenotyped by flow cytometry. Transfection of short-interfering RNAs and treatment with a TLR7/8 agonist altered pathway activities in vitro. Gene expression was analyzed using qRT-PCR, western blotting, and immunohistochemistry. Our findings showed an association between the progression of BC and increased levels of circulating HLA-DR(-)CD33(+) MDSCs. These cells strongly suppress both autologous and analogous CD3(+) T cell proliferation and enter the tumor microenvironment. We also identified increased STAT3 signaling and increased IDO and IL-10 expression in BC-derived MDSCs as immunosuppression mechanisms. Further, STAT3 inhibition and TLR7/8 pathway stimulation reduce the immunosuppressive activity of patient-derived MDSCs on T cells by inducing MDSC repolarization and differentiation into mature myeloid cells. This also alters the expression of critical cytokines and transcription factors in CD3(+) T cells and, importantly, reduces breast cancer cells’ proliferation. Finally, while chemotherapy is able to significantly reduce circulating MDSCs’ level in patients with breast cancer, these MDSCs remained highly T cell-suppressive. We identified a novel molecular mechanism of MDSC-mediated immunosuppression. STAT3 inhibition and TLR7/8 pathway stimulation in MDSCs repolarize and suppress MDSCs from breast cancer patients. This offers new opportunities for BC immunotherapy. Frontiers Media S.A. 2021-02-19 /pmc/articles/PMC7933669/ /pubmed/33679700 http://dx.doi.org/10.3389/fimmu.2020.613215 Text en Copyright © 2021 Safarzadeh, Mohammadi, Mansoori, Duijf, Hashemzadeh, Khaze, Kazemi, Derakhshani, Silvestris and Baradaran http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Immunology
Safarzadeh, Elham
Mohammadi, Ali
Mansoori, Behzad
Duijf, Pascal H. G.
Hashemzadeh, Shahryar
Khaze, Vahid
Kazemi, Tohid
Derakhshani, Afshin
Silvestris, Nicola
Baradaran, Behzad
STAT3 Silencing and TLR7/8 Pathway Activation Repolarize and Suppress Myeloid-Derived Suppressor Cells From Breast Cancer Patients
title STAT3 Silencing and TLR7/8 Pathway Activation Repolarize and Suppress Myeloid-Derived Suppressor Cells From Breast Cancer Patients
title_full STAT3 Silencing and TLR7/8 Pathway Activation Repolarize and Suppress Myeloid-Derived Suppressor Cells From Breast Cancer Patients
title_fullStr STAT3 Silencing and TLR7/8 Pathway Activation Repolarize and Suppress Myeloid-Derived Suppressor Cells From Breast Cancer Patients
title_full_unstemmed STAT3 Silencing and TLR7/8 Pathway Activation Repolarize and Suppress Myeloid-Derived Suppressor Cells From Breast Cancer Patients
title_short STAT3 Silencing and TLR7/8 Pathway Activation Repolarize and Suppress Myeloid-Derived Suppressor Cells From Breast Cancer Patients
title_sort stat3 silencing and tlr7/8 pathway activation repolarize and suppress myeloid-derived suppressor cells from breast cancer patients
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7933669/
https://www.ncbi.nlm.nih.gov/pubmed/33679700
http://dx.doi.org/10.3389/fimmu.2020.613215
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