SNAI1-dependent upregulation of CD73 increases extracellular adenosine release to mediate immune suppression in TNBC
Triple-negative subtype of breast cancer (TNBC) is hallmarked by frequent disease relapse and shows highest mortality rate. Although PD-1/PD-L1 immune checkpoint blockades have recently shown promising clinical benefits, the overall response rate remains largely insufficient. Hence, alternative ther...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-09-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2022.982821/full |
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| author | Meriem Hasmim Malina Xiao Kris Van Moer Akinchan Kumar Alexandra Oniga Michel Mittelbronn Caroline Duhem Anwar Chammout Anwar Chammout Guy Berchem Guy Berchem Jean Paul Thiery Marianna Volpert Brett Hollier Muhammad Zaeem Noman Bassam Janji |
| author_facet | Meriem Hasmim Malina Xiao Kris Van Moer Akinchan Kumar Alexandra Oniga Michel Mittelbronn Caroline Duhem Anwar Chammout Anwar Chammout Guy Berchem Guy Berchem Jean Paul Thiery Marianna Volpert Brett Hollier Muhammad Zaeem Noman Bassam Janji |
| author_sort | Meriem Hasmim |
| collection | DOAJ |
| description | Triple-negative subtype of breast cancer (TNBC) is hallmarked by frequent disease relapse and shows highest mortality rate. Although PD-1/PD-L1 immune checkpoint blockades have recently shown promising clinical benefits, the overall response rate remains largely insufficient. Hence, alternative therapeutic approaches are warranted. Given the immunosuppressive properties of CD73-mediated adenosine release, CD73 blocking approaches are emerging as attractive strategies in cancer immunotherapy. Understanding the precise mechanism regulating the expression of CD73 is required to develop effective anti-CD73-based therapy. Our previous observations demonstrate that the transcription factors driving epithelial-to-mesenchymal transition (EMT-TF) can regulate the expression of several inhibitory immune checkpoints. Here we analyzed the role of the EMT-TF SNAI1 in the regulation of CD73 in TNBC cells. We found that doxycycline-driven SNAI1 expression in the epithelial -like TNBC cell line MDA-MB-468 results in CD73 upregulation by direct binding to the CD73 proximal promoter. SNAI1-dependent upregulation of CD73 leads to increased production and release of extracellular adenosine by TNBC cells and contributes to the enhancement of TNBC immunosuppressive properties. Our data are validated in TNBC samples by showing a positive correlation between the mRNA expression of CD73 and SNAI1. Overall, our results reveal a new CD73 regulation mechanism in TNBC that participates in TNBC-mediated immunosuppression and paves the way for developing new treatment opportunities for CD73-positive TNBC. |
| first_indexed | 2024-04-12T23:19:23Z |
| format | Article |
| id | doaj.art-35d1f9ea5edc46af8039bc9506e5c176 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-04-12T23:19:23Z |
| publishDate | 2022-09-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-35d1f9ea5edc46af8039bc9506e5c1762022-12-22T03:12:35ZengFrontiers Media S.A.Frontiers in Immunology1664-32242022-09-011310.3389/fimmu.2022.982821982821SNAI1-dependent upregulation of CD73 increases extracellular adenosine release to mediate immune suppression in TNBCMeriem Hasmim0Malina Xiao1Kris Van Moer2Akinchan Kumar3Alexandra Oniga4Michel Mittelbronn5Caroline Duhem6Anwar Chammout7Anwar Chammout8Guy Berchem9Guy Berchem10Jean Paul Thiery11Marianna Volpert12Brett Hollier13Muhammad Zaeem Noman14Bassam Janji15Tumor Immunotherapy and Microenvironment Group, Department of Cancer Research, Luxembourg Institute of Health (LIH), Luxembourg, LuxembourgTumor Immunotherapy and Microenvironment Group, Department of Cancer Research, Luxembourg Institute of Health (LIH), Luxembourg, LuxembourgTumor Immunotherapy and Microenvironment Group, Department of Cancer Research, Luxembourg Institute of Health (LIH), Luxembourg, LuxembourgTumor Immunotherapy and Microenvironment Group, Department of Cancer Research, Luxembourg Institute of Health (LIH), Luxembourg, LuxembourgNational Center of Pathology (NCP), Laboratoire Nationale de Santé (LNS), Luxembourg, LuxembourgNational Center of Pathology (NCP), Laboratoire Nationale de Santé (LNS), Luxembourg, LuxembourgDepartment of Hemato-Oncology, Centre Hospitalier du Luxembourg, Luxembourg, LuxembourgDepartment of Oncology, Faculty of Medicine, University of Aleppo, Aleppo, SyriaDepartment of Oncology, Aleppo Hospital University, Aleppo, SyriaTumor Immunotherapy and Microenvironment Group, Department of Cancer Research, Luxembourg Institute of Health (LIH), Luxembourg, LuxembourgDepartment of Hemato-Oncology, Centre Hospitalier du Luxembourg, Luxembourg, LuxembourgGuangzhou Laboratory, Guangzhou, ChinaAustralian Prostate Cancer Research Centre-Queensland (APCRC-Q), School of Biomedical Sciences, Faculty of Health, Princess Alexandra Hospital, Translational Research Institute, Brisbane, QLD, AustraliaAustralian Prostate Cancer Research Centre-Queensland (APCRC-Q), School of Biomedical Sciences, Faculty of Health, Princess Alexandra Hospital, Translational Research Institute, Brisbane, QLD, AustraliaTumor Immunotherapy and Microenvironment Group, Department of Cancer Research, Luxembourg Institute of Health (LIH), Luxembourg, LuxembourgTumor Immunotherapy and Microenvironment Group, Department of Cancer Research, Luxembourg Institute of Health (LIH), Luxembourg, LuxembourgTriple-negative subtype of breast cancer (TNBC) is hallmarked by frequent disease relapse and shows highest mortality rate. Although PD-1/PD-L1 immune checkpoint blockades have recently shown promising clinical benefits, the overall response rate remains largely insufficient. Hence, alternative therapeutic approaches are warranted. Given the immunosuppressive properties of CD73-mediated adenosine release, CD73 blocking approaches are emerging as attractive strategies in cancer immunotherapy. Understanding the precise mechanism regulating the expression of CD73 is required to develop effective anti-CD73-based therapy. Our previous observations demonstrate that the transcription factors driving epithelial-to-mesenchymal transition (EMT-TF) can regulate the expression of several inhibitory immune checkpoints. Here we analyzed the role of the EMT-TF SNAI1 in the regulation of CD73 in TNBC cells. We found that doxycycline-driven SNAI1 expression in the epithelial -like TNBC cell line MDA-MB-468 results in CD73 upregulation by direct binding to the CD73 proximal promoter. SNAI1-dependent upregulation of CD73 leads to increased production and release of extracellular adenosine by TNBC cells and contributes to the enhancement of TNBC immunosuppressive properties. Our data are validated in TNBC samples by showing a positive correlation between the mRNA expression of CD73 and SNAI1. Overall, our results reveal a new CD73 regulation mechanism in TNBC that participates in TNBC-mediated immunosuppression and paves the way for developing new treatment opportunities for CD73-positive TNBC.https://www.frontiersin.org/articles/10.3389/fimmu.2022.982821/fullCD73SNAI1epithelial-to-mesenchymal transitionadenosineanti-tumor immune responseimmunotherapy |
| spellingShingle | Meriem Hasmim Malina Xiao Kris Van Moer Akinchan Kumar Alexandra Oniga Michel Mittelbronn Caroline Duhem Anwar Chammout Anwar Chammout Guy Berchem Guy Berchem Jean Paul Thiery Marianna Volpert Brett Hollier Muhammad Zaeem Noman Bassam Janji SNAI1-dependent upregulation of CD73 increases extracellular adenosine release to mediate immune suppression in TNBC Frontiers in Immunology CD73 SNAI1 epithelial-to-mesenchymal transition adenosine anti-tumor immune response immunotherapy |
| title | SNAI1-dependent upregulation of CD73 increases extracellular adenosine release to mediate immune suppression in TNBC |
| title_full | SNAI1-dependent upregulation of CD73 increases extracellular adenosine release to mediate immune suppression in TNBC |
| title_fullStr | SNAI1-dependent upregulation of CD73 increases extracellular adenosine release to mediate immune suppression in TNBC |
| title_full_unstemmed | SNAI1-dependent upregulation of CD73 increases extracellular adenosine release to mediate immune suppression in TNBC |
| title_short | SNAI1-dependent upregulation of CD73 increases extracellular adenosine release to mediate immune suppression in TNBC |
| title_sort | snai1 dependent upregulation of cd73 increases extracellular adenosine release to mediate immune suppression in tnbc |
| topic | CD73 SNAI1 epithelial-to-mesenchymal transition adenosine anti-tumor immune response immunotherapy |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2022.982821/full |
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