Canine Transforming Growth Factor-β Receptor 2-Ig: A Potential Candidate Biologic for Melanoma Treatment That Reverses Transforming Growth Factor-β1 Immunosuppression
Cancer cells can evade host immune systems via multiple mechanisms. Transforming growth factor beta 1 (TGF-β1) is an immunosuppressive cytokine that induces regulatory T cell (Tregs) differentiation and is involved in immune evasion mechanisms in cancer. The inhibition of the TGF-β1 signaling pathwa...
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Format: | Article |
Language: | English |
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Frontiers Media S.A.
2021-06-01
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Series: | Frontiers in Veterinary Science |
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Online Access: | https://www.frontiersin.org/articles/10.3389/fvets.2021.656715/full |
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Article |
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DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Hiroto Takeuchi Satoru Konnai Satoru Konnai Naoya Maekawa Satoshi Takagi Satoshi Takagi Hiroshi Ohta Noboru Sasaki Sangho Kim Tomohiro Okagawa Yasuhiko Suzuki Yasuhiko Suzuki Yasuhiko Suzuki Shiro Murata Shiro Murata Kazuhiko Ohashi Kazuhiko Ohashi |
spellingShingle |
Hiroto Takeuchi Satoru Konnai Satoru Konnai Naoya Maekawa Satoshi Takagi Satoshi Takagi Hiroshi Ohta Noboru Sasaki Sangho Kim Tomohiro Okagawa Yasuhiko Suzuki Yasuhiko Suzuki Yasuhiko Suzuki Shiro Murata Shiro Murata Kazuhiko Ohashi Kazuhiko Ohashi Canine Transforming Growth Factor-β Receptor 2-Ig: A Potential Candidate Biologic for Melanoma Treatment That Reverses Transforming Growth Factor-β1 Immunosuppression Frontiers in Veterinary Science canine melanoma immunosuppression TGF-β1 biologic cancer immunotherapy |
author_facet |
Hiroto Takeuchi Satoru Konnai Satoru Konnai Naoya Maekawa Satoshi Takagi Satoshi Takagi Hiroshi Ohta Noboru Sasaki Sangho Kim Tomohiro Okagawa Yasuhiko Suzuki Yasuhiko Suzuki Yasuhiko Suzuki Shiro Murata Shiro Murata Kazuhiko Ohashi Kazuhiko Ohashi |
author_sort |
Hiroto Takeuchi |
title |
Canine Transforming Growth Factor-β Receptor 2-Ig: A Potential Candidate Biologic for Melanoma Treatment That Reverses Transforming Growth Factor-β1 Immunosuppression |
title_short |
Canine Transforming Growth Factor-β Receptor 2-Ig: A Potential Candidate Biologic for Melanoma Treatment That Reverses Transforming Growth Factor-β1 Immunosuppression |
title_full |
Canine Transforming Growth Factor-β Receptor 2-Ig: A Potential Candidate Biologic for Melanoma Treatment That Reverses Transforming Growth Factor-β1 Immunosuppression |
title_fullStr |
Canine Transforming Growth Factor-β Receptor 2-Ig: A Potential Candidate Biologic for Melanoma Treatment That Reverses Transforming Growth Factor-β1 Immunosuppression |
title_full_unstemmed |
Canine Transforming Growth Factor-β Receptor 2-Ig: A Potential Candidate Biologic for Melanoma Treatment That Reverses Transforming Growth Factor-β1 Immunosuppression |
title_sort |
canine transforming growth factor-β receptor 2-ig: a potential candidate biologic for melanoma treatment that reverses transforming growth factor-β1 immunosuppression |
publisher |
Frontiers Media S.A. |
series |
Frontiers in Veterinary Science |
issn |
2297-1769 |
publishDate |
2021-06-01 |
description |
Cancer cells can evade host immune systems via multiple mechanisms. Transforming growth factor beta 1 (TGF-β1) is an immunosuppressive cytokine that induces regulatory T cell (Tregs) differentiation and is involved in immune evasion mechanisms in cancer. The inhibition of the TGF-β1 signaling pathway can suppress cancer progression and metastasis through the modulation of anticancer immune responses. However, to best of our knowledge, no implementation of treatments targeting TGF-β1 has been reported in dog cancers. This study aimed to examine whether TGF-β1 is upregulated in canine cancers. We measured TGF-β1 concentrations in culture supernatants of canine melanoma cell lines and in serum samples from dogs with oral malignant melanoma. TGF-β1 production was observed in several cell lines, and serum TGF-β1 levels were elevated in dogs with oral malignant melanoma. Interestingly, the addition of recombinant TGF-β1 to canine peripheral blood mononuclear cell cultures decreased Th1 cytokine production and increased differentiation of CD4+CD25+Foxp3+ lymphocytes, suggesting that TGF-β1 is immunosuppressive in canine immune systems. We developed a decoy receptor for TGF-β, namely TGF-βRII-Ig, by identifying an open reading frame of the canine TGFBR2 gene. TGF-βRII-Ig was prepared as a recombinant fusion protein of the extracellular region of canine TGF-βRII and the Fc region of canine IgG-B. As expected, TGF-βRII-Ig bound to TGF-β1. In the presence of TGF-β1, the treatment with TGF-βRII-Ig increased Th1 cytokine production and decreased the differentiation of CD4+CD25+Foxp3+ lymphocytes. Our results suggest that TGF-βRII-Ig competitively inhibits the immunosuppressive effects of TGF-β1 and thereby activates immune responses. This study demonstrated the potential of TGF-βRII-Ig as a novel biologic for canine melanoma. |
topic |
canine melanoma immunosuppression TGF-β1 biologic cancer immunotherapy |
url |
https://www.frontiersin.org/articles/10.3389/fvets.2021.656715/full |
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doaj-da68eb78c1074fe18f910eac09e1c3da2021-06-14T05:57:06ZengFrontiers Media S.A.Frontiers in Veterinary Science2297-17692021-06-01810.3389/fvets.2021.656715656715Canine Transforming Growth Factor-β Receptor 2-Ig: A Potential Candidate Biologic for Melanoma Treatment That Reverses Transforming Growth Factor-β1 ImmunosuppressionHiroto Takeuchi0Satoru Konnai1Satoru Konnai2Naoya Maekawa3Satoshi Takagi4Satoshi Takagi5Hiroshi Ohta6Noboru Sasaki7Sangho Kim8Tomohiro Okagawa9Yasuhiko Suzuki10Yasuhiko Suzuki11Yasuhiko Suzuki12Shiro Murata13Shiro Murata14Kazuhiko Ohashi15Kazuhiko Ohashi16Department of Disease Control, Faculty of Veterinary Medicine, Hokkaido University, Sapporo, JapanDepartment of Disease Control, Faculty of Veterinary Medicine, Hokkaido University, Sapporo, JapanDepartment of Advanced Pharmaceutics, Faculty of Veterinary Medicine, Hokkaido University, Sapporo, JapanDepartment of Advanced Pharmaceutics, Faculty of Veterinary Medicine, Hokkaido University, Sapporo, JapanDepartment of Clinical Sciences, Faculty of Veterinary Medicine, Hokkaido University, Sapporo, JapanDepartment of Veterinary Surgery, School of Veterinary Medicine, Azabu University, Sagamihara, JapanDepartment of Clinical Sciences, Faculty of Veterinary Medicine, Hokkaido University, Sapporo, JapanDepartment of Clinical Sciences, Faculty of Veterinary Medicine, Hokkaido University, Sapporo, JapanDepartment of Clinical Sciences, Faculty of Veterinary Medicine, Hokkaido University, Sapporo, JapanDepartment of Advanced Pharmaceutics, Faculty of Veterinary Medicine, Hokkaido University, Sapporo, JapanDepartment of Advanced Pharmaceutics, Faculty of Veterinary Medicine, Hokkaido University, Sapporo, JapanResearch Center for Zoonosis Control, Hokkaido University, Sapporo, JapanGlobal Station for Zoonosis Control, Global Institution for Collaborative Research and Education, Hokkaido University, Sapporo, JapanDepartment of Disease Control, Faculty of Veterinary Medicine, Hokkaido University, Sapporo, JapanDepartment of Advanced Pharmaceutics, Faculty of Veterinary Medicine, Hokkaido University, Sapporo, JapanDepartment of Disease Control, Faculty of Veterinary Medicine, Hokkaido University, Sapporo, JapanDepartment of Advanced Pharmaceutics, Faculty of Veterinary Medicine, Hokkaido University, Sapporo, JapanCancer cells can evade host immune systems via multiple mechanisms. Transforming growth factor beta 1 (TGF-β1) is an immunosuppressive cytokine that induces regulatory T cell (Tregs) differentiation and is involved in immune evasion mechanisms in cancer. The inhibition of the TGF-β1 signaling pathway can suppress cancer progression and metastasis through the modulation of anticancer immune responses. However, to best of our knowledge, no implementation of treatments targeting TGF-β1 has been reported in dog cancers. This study aimed to examine whether TGF-β1 is upregulated in canine cancers. We measured TGF-β1 concentrations in culture supernatants of canine melanoma cell lines and in serum samples from dogs with oral malignant melanoma. TGF-β1 production was observed in several cell lines, and serum TGF-β1 levels were elevated in dogs with oral malignant melanoma. Interestingly, the addition of recombinant TGF-β1 to canine peripheral blood mononuclear cell cultures decreased Th1 cytokine production and increased differentiation of CD4+CD25+Foxp3+ lymphocytes, suggesting that TGF-β1 is immunosuppressive in canine immune systems. We developed a decoy receptor for TGF-β, namely TGF-βRII-Ig, by identifying an open reading frame of the canine TGFBR2 gene. TGF-βRII-Ig was prepared as a recombinant fusion protein of the extracellular region of canine TGF-βRII and the Fc region of canine IgG-B. As expected, TGF-βRII-Ig bound to TGF-β1. In the presence of TGF-β1, the treatment with TGF-βRII-Ig increased Th1 cytokine production and decreased the differentiation of CD4+CD25+Foxp3+ lymphocytes. Our results suggest that TGF-βRII-Ig competitively inhibits the immunosuppressive effects of TGF-β1 and thereby activates immune responses. This study demonstrated the potential of TGF-βRII-Ig as a novel biologic for canine melanoma.https://www.frontiersin.org/articles/10.3389/fvets.2021.656715/fullcaninemelanomaimmunosuppressionTGF-β1biologiccancer immunotherapy |