B7-H3 Suppresses Antitumor Immunity via the CCL2–CCR2–M2 Macrophage Axis and Contributes to Ovarian Cancer Progression
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- Taito Miyamoto
- 1Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine, Kyoto, Japan.
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- Ryusuke Murakami
- 1Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine, Kyoto, Japan.
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- Junzo Hamanishi
- 1Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine, Kyoto, Japan.
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- Kenji Tanigaki
- 3Research Institute, Shiga Medical Center, Shiga, Japan.
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- Yuko Hosoe
- 1Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine, Kyoto, Japan.
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- Nathan Mise
- 4Department of Environmental and Preventive Medicine, Jichi Medical University, Shimotsuke, Japan.
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- Shiro Takamatsu
- 1Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine, Kyoto, Japan.
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- Yuka Mise
- 1Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine, Kyoto, Japan.
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- Masayo Ukita
- 1Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine, Kyoto, Japan.
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- Mana Taki
- 1Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine, Kyoto, Japan.
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- Koji Yamanoi
- 1Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine, Kyoto, Japan.
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- Naoki Horikawa
- 1Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine, Kyoto, Japan.
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- Kaoru Abiko
- 1Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine, Kyoto, Japan.
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- Ken Yamaguchi
- 1Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine, Kyoto, Japan.
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- Tsukasa Baba
- 7Department of Obstetrics and Gynecology, Iwate Medical University School of Medicine, Iwate, Japan.
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- Noriomi Matsumura
- 8Department of Obstetrics and Gynecology, Kindai University School of Medicine, Higashiosaka, Japan.
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- Masaki Mandai
- 1Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Description
<jats:title>Abstract</jats:title> <jats:sec> <jats:title /> <jats:p>New approaches beyond PD-1/PD-L1 inhibition are required to target the immunologically diverse tumor microenvironment (TME) in high-grade serous ovarian cancer (HGSOC). In this study, we explored the immunosuppressive effect of B7-H3 (CD276) via the CCL2–CCR2–M2 macrophage axis and its potential as a therapeutic target. Transcriptome analysis revealed that B7-H3 is highly expressed in PD-L1–low, nonimmunoreactive HGSOC tumors, and its expression negatively correlated with an IFNγ signature, which reflects the tumor immune reactivity. In syngeneic mouse models, B7-H3 (Cd276) knockout (KO) in tumor cells, but not in stromal cells, suppressed tumor progression, with a reduced number of M2 macrophages and an increased number of IFNγ+CD8+ T cells. CCL2 expression was downregulated in the B7-H3 KO tumor cell lines. Inhibition of the CCL2–CCR2 axis partly negated the effects of B7-H3 suppression on M2 macrophage migration and differentiation, and tumor progression. In patients with HGSOC, B7-H3 expression positively correlated with CCL2 expression and M2 macrophage abundance, and patients with B7-H3–high tumors had fewer tumoral IFNγ+CD8+ T cells and poorer prognosis than patients with B7-H3–low tumors. Thus, B7-H3 expression in tumor cells contributes to CCL2–CCR2–M2 macrophage axis–mediated immunosuppression and tumor progression. These findings provide new insights into the immunologic TME and could aid the development of new therapeutic approaches against the unfavorable HGSOC phenotype.</jats:p> </jats:sec>
Journal
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- Cancer Immunology Research
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Cancer Immunology Research 10 (1), 56-69, 2021-11-19
American Association for Cancer Research (AACR)
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Details 詳細情報について
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- CRID
- 1360013168753082496
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- ISSN
- 23266074
- 23266066
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- Data Source
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- Crossref
- KAKEN