Novel role of microphthalmia-associated transcription factor in modulating the differentiation and immunosuppressive functions of myeloid-derived suppressor cells
Background Microphthalmia-associated transcription factor (MITF) is a master regulator of melanogenesis and is mainly expressed in melanoma cells. MITF has also been reported to be expressed in non-pigmented cells, such as osteoclasts, mast cells, and B cells. However, the roles of MITF in immunosup...
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| Language: | English |
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BMJ Publishing Group
2023-01-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/11/1/e005699.full |
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| author | Yoon Kyung Jeon Aram Lee Haesun Park Soyoung Lim Jihyun Lim Jaemoon Koh Young Yang Myeong-Sok Lee Jong-Seok Lim |
| author_facet | Yoon Kyung Jeon Aram Lee Haesun Park Soyoung Lim Jihyun Lim Jaemoon Koh Young Yang Myeong-Sok Lee Jong-Seok Lim |
| author_sort | Yoon Kyung Jeon |
| collection | DOAJ |
| description | Background Microphthalmia-associated transcription factor (MITF) is a master regulator of melanogenesis and is mainly expressed in melanoma cells. MITF has also been reported to be expressed in non-pigmented cells, such as osteoclasts, mast cells, and B cells. However, the roles of MITF in immunosuppressive myeloid cells, including myeloid-derived suppressor cells (MDSCs), remain unclear. Here, we investigated the role of MITF in the differentiation process of MDSCs during tumor development.Methods In vitro-generated murine MDSCs and primary MDSCs from breast cancer-bearing mice or lung carcinoma-bearing mice were used to determine the expression level of MITF and the activity of MDSCs. Additionally, we investigated whether in vivo tumor growth can be differentially regulated by coinjection of MDSCs in which MITF expression is modulated by small molecules. Furthermore, the number of MITF+ monocytic (MO)-MDSCs was examined in human tumor tissues or tumor-free lymph nodes by immunohistochemistry (IHC).Results The expression of MITF was strongly increased in MO-MDSCs from tumors of breast cancer-bearing mice compared with polymorphonuclear MDSCs. We found that MITF expression in MDSCs was markedly induced in the tumor microenvironment (TME) and related to the functional activity of MDSCs. MITF overexpression in myeloid cells increased the expression of MDSC activity markers and effectively inhibited T-cell proliferation compared with those of control MDSCs, whereas shRNA-mediated knockdown of MITF in myeloid cells altered the immunosuppressive function of MDSCs. Modulation of MITF expression by small molecules affected the differentiation and immunosuppressive function of MDSCs. While increased MITF expression in MDSCs promoted breast cancer progression and CD4+ or CD8+ T-cell dysfunction, decreased MITF expression in MDSCs suppressed tumor progression and enhanced T-cell activation. Furthermore, IHC staining of human tumor tissues revealed that MITF+ MO-MDSCs are more frequently observed in tumor tissues than in tumor-free draining lymph nodes obtained from patients with cancer.Conclusions Our results indicate that MITF regulates the differentiation and function of MDSCs and can be a novel therapeutic target for modulating MDSC activity in immunosuppressive TMEs. |
| format | Article |
| id | doaj-art-4947cad4220c4b97aa81a5d1c7cc84a3 |
| institution | Kabale University |
| issn | 2051-1426 |
| language | English |
| publishDate | 2023-01-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-4947cad4220c4b97aa81a5d1c7cc84a32025-01-29T11:00:08ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262023-01-0111110.1136/jitc-2022-005699Novel role of microphthalmia-associated transcription factor in modulating the differentiation and immunosuppressive functions of myeloid-derived suppressor cellsYoon Kyung Jeon0Aram Lee1Haesun Park2Soyoung Lim3Jihyun Lim4Jaemoon Koh5Young Yang6Myeong-Sok Lee7Jong-Seok Lim87 Department of Pathology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, South KoreaDepartment of Biological Science, Sookmyung Women`s University College of Science, Seoul, KoreaDepartment of Biological Science, Sookmyung Women`s University College of Science, Seoul, KoreaDepartment of Biological Science, Sookmyung Women`s University College of Science, Seoul, KoreaDepartment of Biological Science, Sookmyung Women`s University College of Science, Seoul, KoreaDepartment of Pathology, Seoul National University College of Medicine, Seoul, KoreaDepartment of Biological Science, Sookmyung Women`s University College of Science, Seoul, KoreaDepartment of Biological Science, Sookmyung Women`s University College of Science, Seoul, KoreaDepartment of Biological Science, Sookmyung Women`s University College of Science, Seoul, KoreaBackground Microphthalmia-associated transcription factor (MITF) is a master regulator of melanogenesis and is mainly expressed in melanoma cells. MITF has also been reported to be expressed in non-pigmented cells, such as osteoclasts, mast cells, and B cells. However, the roles of MITF in immunosuppressive myeloid cells, including myeloid-derived suppressor cells (MDSCs), remain unclear. Here, we investigated the role of MITF in the differentiation process of MDSCs during tumor development.Methods In vitro-generated murine MDSCs and primary MDSCs from breast cancer-bearing mice or lung carcinoma-bearing mice were used to determine the expression level of MITF and the activity of MDSCs. Additionally, we investigated whether in vivo tumor growth can be differentially regulated by coinjection of MDSCs in which MITF expression is modulated by small molecules. Furthermore, the number of MITF+ monocytic (MO)-MDSCs was examined in human tumor tissues or tumor-free lymph nodes by immunohistochemistry (IHC).Results The expression of MITF was strongly increased in MO-MDSCs from tumors of breast cancer-bearing mice compared with polymorphonuclear MDSCs. We found that MITF expression in MDSCs was markedly induced in the tumor microenvironment (TME) and related to the functional activity of MDSCs. MITF overexpression in myeloid cells increased the expression of MDSC activity markers and effectively inhibited T-cell proliferation compared with those of control MDSCs, whereas shRNA-mediated knockdown of MITF in myeloid cells altered the immunosuppressive function of MDSCs. Modulation of MITF expression by small molecules affected the differentiation and immunosuppressive function of MDSCs. While increased MITF expression in MDSCs promoted breast cancer progression and CD4+ or CD8+ T-cell dysfunction, decreased MITF expression in MDSCs suppressed tumor progression and enhanced T-cell activation. Furthermore, IHC staining of human tumor tissues revealed that MITF+ MO-MDSCs are more frequently observed in tumor tissues than in tumor-free draining lymph nodes obtained from patients with cancer.Conclusions Our results indicate that MITF regulates the differentiation and function of MDSCs and can be a novel therapeutic target for modulating MDSC activity in immunosuppressive TMEs.https://jitc.bmj.com/content/11/1/e005699.full |
| spellingShingle | Yoon Kyung Jeon Aram Lee Haesun Park Soyoung Lim Jihyun Lim Jaemoon Koh Young Yang Myeong-Sok Lee Jong-Seok Lim Novel role of microphthalmia-associated transcription factor in modulating the differentiation and immunosuppressive functions of myeloid-derived suppressor cells Journal for ImmunoTherapy of Cancer |
| title | Novel role of microphthalmia-associated transcription factor in modulating the differentiation and immunosuppressive functions of myeloid-derived suppressor cells |
| title_full | Novel role of microphthalmia-associated transcription factor in modulating the differentiation and immunosuppressive functions of myeloid-derived suppressor cells |
| title_fullStr | Novel role of microphthalmia-associated transcription factor in modulating the differentiation and immunosuppressive functions of myeloid-derived suppressor cells |
| title_full_unstemmed | Novel role of microphthalmia-associated transcription factor in modulating the differentiation and immunosuppressive functions of myeloid-derived suppressor cells |
| title_short | Novel role of microphthalmia-associated transcription factor in modulating the differentiation and immunosuppressive functions of myeloid-derived suppressor cells |
| title_sort | novel role of microphthalmia associated transcription factor in modulating the differentiation and immunosuppressive functions of myeloid derived suppressor cells |
| url | https://jitc.bmj.com/content/11/1/e005699.full |
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