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B7-H3 Suppresses Antitumor Immunity via the CCL2–CCR2–M2 Macrophage Axis and Contributes to Ovarian Cancer Progression

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...

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Autores principales: Miyamoto, Taito, Murakami, Ryusuke, Hamanishi, Junzo, Tanigaki, Kenji, Hosoe, Yuko, Mise, Nathan, Takamatsu, Shiro, Mise, Yuka, Ukita, Masayo, Taki, Mana, Yamanoi, Koji, Horikawa, Naoki, Abiko, Kaoru, Yamaguchi, Ken, Baba, Tsukasa, Matsumura, Noriomi, Mandai, Masaki
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Association for Cancer Research 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9414298/
https://www.ncbi.nlm.nih.gov/pubmed/34799346
http://dx.doi.org/10.1158/2326-6066.CIR-21-0407
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author Miyamoto, Taito
Murakami, Ryusuke
Hamanishi, Junzo
Tanigaki, Kenji
Hosoe, Yuko
Mise, Nathan
Takamatsu, Shiro
Mise, Yuka
Ukita, Masayo
Taki, Mana
Yamanoi, Koji
Horikawa, Naoki
Abiko, Kaoru
Yamaguchi, Ken
Baba, Tsukasa
Matsumura, Noriomi
Mandai, Masaki
author_facet Miyamoto, Taito
Murakami, Ryusuke
Hamanishi, Junzo
Tanigaki, Kenji
Hosoe, Yuko
Mise, Nathan
Takamatsu, Shiro
Mise, Yuka
Ukita, Masayo
Taki, Mana
Yamanoi, Koji
Horikawa, Naoki
Abiko, Kaoru
Yamaguchi, Ken
Baba, Tsukasa
Matsumura, Noriomi
Mandai, Masaki
author_sort Miyamoto, Taito
collection PubMed
description 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.
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spelling pubmed-94142982023-01-05 B7-H3 Suppresses Antitumor Immunity via the CCL2–CCR2–M2 Macrophage Axis and Contributes to Ovarian Cancer Progression Miyamoto, Taito Murakami, Ryusuke Hamanishi, Junzo Tanigaki, Kenji Hosoe, Yuko Mise, Nathan Takamatsu, Shiro Mise, Yuka Ukita, Masayo Taki, Mana Yamanoi, Koji Horikawa, Naoki Abiko, Kaoru Yamaguchi, Ken Baba, Tsukasa Matsumura, Noriomi Mandai, Masaki Cancer Immunol Res Research Articles 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. American Association for Cancer Research 2022-01-01 2021-11-19 /pmc/articles/PMC9414298/ /pubmed/34799346 http://dx.doi.org/10.1158/2326-6066.CIR-21-0407 Text en ©2021 The Authors; Published by the American Association for Cancer Research https://creativecommons.org/licenses/by-nc-nd/4.0/This open access article is distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) license.
spellingShingle Research Articles
Miyamoto, Taito
Murakami, Ryusuke
Hamanishi, Junzo
Tanigaki, Kenji
Hosoe, Yuko
Mise, Nathan
Takamatsu, Shiro
Mise, Yuka
Ukita, Masayo
Taki, Mana
Yamanoi, Koji
Horikawa, Naoki
Abiko, Kaoru
Yamaguchi, Ken
Baba, Tsukasa
Matsumura, Noriomi
Mandai, Masaki
B7-H3 Suppresses Antitumor Immunity via the CCL2–CCR2–M2 Macrophage Axis and Contributes to Ovarian Cancer Progression
title B7-H3 Suppresses Antitumor Immunity via the CCL2–CCR2–M2 Macrophage Axis and Contributes to Ovarian Cancer Progression
title_full B7-H3 Suppresses Antitumor Immunity via the CCL2–CCR2–M2 Macrophage Axis and Contributes to Ovarian Cancer Progression
title_fullStr B7-H3 Suppresses Antitumor Immunity via the CCL2–CCR2–M2 Macrophage Axis and Contributes to Ovarian Cancer Progression
title_full_unstemmed B7-H3 Suppresses Antitumor Immunity via the CCL2–CCR2–M2 Macrophage Axis and Contributes to Ovarian Cancer Progression
title_short B7-H3 Suppresses Antitumor Immunity via the CCL2–CCR2–M2 Macrophage Axis and Contributes to Ovarian Cancer Progression
title_sort b7-h3 suppresses antitumor immunity via the ccl2–ccr2–m2 macrophage axis and contributes to ovarian cancer progression
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9414298/
https://www.ncbi.nlm.nih.gov/pubmed/34799346
http://dx.doi.org/10.1158/2326-6066.CIR-21-0407
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