Immunotherapy with 4-1BBL-Expressing iPS Cell‐Derived Myeloid Lines Amplifies Antigen-Specific T Cell Infiltration in Advanced Melanoma

We have established an immune cell therapy with immortalized induced pluripotent stem-cell–derived myeloid lines (iPS-ML). The benefits of using iPS-ML are the infinite proliferative capacity and ease of genetic modification. In this study, we introduced 4-1BBL gene to iPS-ML (iPS-ML-41BBL). The ana...

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Main Authors: Haruka Kuriyama, Satoshi Fukushima, Toshihiro Kimura, Hisashi Kanemaru, Azusa Miyashita, Etsuko Okada, Yosuke Kubo, Satoshi Nakahara, Aki Tokuzumi, Yuki Nishimura, Ikko Kajihara, Katsunari Makino, Jun Aoi, Shinichi Masuguchi, Hirotake Tsukamoto, Takashi Inozume, Rong Zhang, Tetsuya Nakatsura, Yasushi Uemura, Satoru Senju, Hironobu Ihn
Format: Article
Language:English
Published: MDPI AG 2021-02-01
Series:International Journal of Molecular Sciences
Subjects:
Online Access:https://www.mdpi.com/1422-0067/22/4/1958
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language English
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author Haruka Kuriyama
Satoshi Fukushima
Toshihiro Kimura
Hisashi Kanemaru
Azusa Miyashita
Etsuko Okada
Yosuke Kubo
Satoshi Nakahara
Aki Tokuzumi
Yuki Nishimura
Ikko Kajihara
Katsunari Makino
Jun Aoi
Shinichi Masuguchi
Hirotake Tsukamoto
Takashi Inozume
Rong Zhang
Tetsuya Nakatsura
Yasushi Uemura
Satoru Senju
Hironobu Ihn
spellingShingle Haruka Kuriyama
Satoshi Fukushima
Toshihiro Kimura
Hisashi Kanemaru
Azusa Miyashita
Etsuko Okada
Yosuke Kubo
Satoshi Nakahara
Aki Tokuzumi
Yuki Nishimura
Ikko Kajihara
Katsunari Makino
Jun Aoi
Shinichi Masuguchi
Hirotake Tsukamoto
Takashi Inozume
Rong Zhang
Tetsuya Nakatsura
Yasushi Uemura
Satoru Senju
Hironobu Ihn
Immunotherapy with 4-1BBL-Expressing iPS Cell‐Derived Myeloid Lines Amplifies Antigen-Specific T Cell Infiltration in Advanced Melanoma
International Journal of Molecular Sciences
iPS cells
4-1BBL
CXCR6
melanoma
immune cell therapy
author_facet Haruka Kuriyama
Satoshi Fukushima
Toshihiro Kimura
Hisashi Kanemaru
Azusa Miyashita
Etsuko Okada
Yosuke Kubo
Satoshi Nakahara
Aki Tokuzumi
Yuki Nishimura
Ikko Kajihara
Katsunari Makino
Jun Aoi
Shinichi Masuguchi
Hirotake Tsukamoto
Takashi Inozume
Rong Zhang
Tetsuya Nakatsura
Yasushi Uemura
Satoru Senju
Hironobu Ihn
author_sort Haruka Kuriyama
title Immunotherapy with 4-1BBL-Expressing iPS Cell‐Derived Myeloid Lines Amplifies Antigen-Specific T Cell Infiltration in Advanced Melanoma
title_short Immunotherapy with 4-1BBL-Expressing iPS Cell‐Derived Myeloid Lines Amplifies Antigen-Specific T Cell Infiltration in Advanced Melanoma
title_full Immunotherapy with 4-1BBL-Expressing iPS Cell‐Derived Myeloid Lines Amplifies Antigen-Specific T Cell Infiltration in Advanced Melanoma
title_fullStr Immunotherapy with 4-1BBL-Expressing iPS Cell‐Derived Myeloid Lines Amplifies Antigen-Specific T Cell Infiltration in Advanced Melanoma
title_full_unstemmed Immunotherapy with 4-1BBL-Expressing iPS Cell‐Derived Myeloid Lines Amplifies Antigen-Specific T Cell Infiltration in Advanced Melanoma
title_sort immunotherapy with 4-1bbl-expressing ips cell‐derived myeloid lines amplifies antigen-specific t cell infiltration in advanced melanoma
publisher MDPI AG
series International Journal of Molecular Sciences
issn 1661-6596
1422-0067
publishDate 2021-02-01
description We have established an immune cell therapy with immortalized induced pluripotent stem-cell–derived myeloid lines (iPS-ML). The benefits of using iPS-ML are the infinite proliferative capacity and ease of genetic modification. In this study, we introduced 4-1BBL gene to iPS-ML (iPS-ML-41BBL). The analysis of the cell-surface molecules showed that the expression of CD86 was upregulated in iPS-ML-41BBL more than that in control iPS-ML. Cytokine array analysis was performed using supernatants of the spleen cells that were cocultured with iPS-ML or iPS-ML-41BBL. Multiple cytokines that are beneficial to cancer immunotherapy were upregulated. Peritoneal injections of iPS-ML-41BBL inhibited tumor growth of peritoneally disseminated mouse melanoma and prolonged survival of mice compared to that of iPS-ML. Furthermore, the numbers of antigen-specific CD8<sup>+</sup> T cells were significantly increased in the spleen and tumor tissues treated with epitope peptide-pulsed iPS-ML-41BBL compared to those treated with control iPS-ML. The number of CXCR6-positive T cells were increased in the tumor tissues after treatment with iPS-ML-41BBL compared to that with control iPS-ML. These results suggest that iPS-ML-41BBL could activate antigen-specific T cells and promote their infiltration into the tumor tissues. Thus, iPS-ML-41BBL may be a candidate for future immune cell therapy aiming to change immunological “cold tumor” to “hot tumor.”
topic iPS cells
4-1BBL
CXCR6
melanoma
immune cell therapy
url https://www.mdpi.com/1422-0067/22/4/1958
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spelling doaj-af921cc729da4155a4382b4092d3f07a2021-02-17T00:04:29ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-02-01221958195810.3390/ijms22041958Immunotherapy with 4-1BBL-Expressing iPS Cell‐Derived Myeloid Lines Amplifies Antigen-Specific T Cell Infiltration in Advanced MelanomaHaruka Kuriyama0Satoshi Fukushima1Toshihiro Kimura2Hisashi Kanemaru3Azusa Miyashita4Etsuko Okada5Yosuke Kubo6Satoshi Nakahara7Aki Tokuzumi8Yuki Nishimura9Ikko Kajihara10Katsunari Makino11Jun Aoi12Shinichi Masuguchi13Hirotake Tsukamoto14Takashi Inozume15Rong Zhang16Tetsuya Nakatsura17Yasushi Uemura18Satoru Senju19Hironobu Ihn20Department of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, JapanDepartment of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, JapanDepartment of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, JapanDepartment of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, JapanDepartment of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, JapanDepartment of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, JapanDepartment of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, JapanDepartment of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, JapanDepartment of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, JapanDepartment of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, JapanDepartment of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, JapanDepartment of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, JapanDepartment of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, JapanDepartment of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, JapanDepartment of Immunology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-8556, JapanDepartment of Dermatology, Graduate School of Medicine, Chiba University, Chiba 260-8677, JapanDivision of Cancer Immunotherapy, Exploratory Oncology Research & Clinical Trial Center, National Cancer Center (NCC), Kashiwa 277-8577, JapanDivision of Cancer Immunotherapy, Exploratory Oncology Research & Clinical Trial Center, National Cancer Center (NCC), Kashiwa 277-8577, JapanDivision of Cancer Immunotherapy, Exploratory Oncology Research & Clinical Trial Center, National Cancer Center (NCC), Kashiwa 277-8577, JapanDepartment of Immunogenetics, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-8556, JapanDepartment of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, JapanWe have established an immune cell therapy with immortalized induced pluripotent stem-cell–derived myeloid lines (iPS-ML). The benefits of using iPS-ML are the infinite proliferative capacity and ease of genetic modification. In this study, we introduced 4-1BBL gene to iPS-ML (iPS-ML-41BBL). The analysis of the cell-surface molecules showed that the expression of CD86 was upregulated in iPS-ML-41BBL more than that in control iPS-ML. Cytokine array analysis was performed using supernatants of the spleen cells that were cocultured with iPS-ML or iPS-ML-41BBL. Multiple cytokines that are beneficial to cancer immunotherapy were upregulated. Peritoneal injections of iPS-ML-41BBL inhibited tumor growth of peritoneally disseminated mouse melanoma and prolonged survival of mice compared to that of iPS-ML. Furthermore, the numbers of antigen-specific CD8<sup>+</sup> T cells were significantly increased in the spleen and tumor tissues treated with epitope peptide-pulsed iPS-ML-41BBL compared to those treated with control iPS-ML. The number of CXCR6-positive T cells were increased in the tumor tissues after treatment with iPS-ML-41BBL compared to that with control iPS-ML. These results suggest that iPS-ML-41BBL could activate antigen-specific T cells and promote their infiltration into the tumor tissues. Thus, iPS-ML-41BBL may be a candidate for future immune cell therapy aiming to change immunological “cold tumor” to “hot tumor.”https://www.mdpi.com/1422-0067/22/4/1958iPS cells4-1BBLCXCR6melanomaimmune cell therapy