B7-H3 Suppresses Antitumor Immunity via the CCL2-CCR2-M2 Macrophage Axis and Contributes to Ovarian Cancer Progression.
B7-H3 Suppresses Antitumor Immunity via the CCL2-CCR2-M2 Macrophage Axis and Contributes to Ovarian Cancer Progression.
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DOI：
10.1158/2326-6066.cir-21-0407
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发表时间：
2022-01
影响因子：
10.1
通讯作者：
Mandai, Masaki
中科院分区：
文献类型：
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作者：
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
需要超越PD-1/PD-L1抑制的新方法来靶向高级别浆液性卵巢癌（HGSOC）中免疫多样性肿瘤微环境（TME）。在这项研究中，我们探索了B7-H3（CD 276）通过CCL 2-CCR 2-M2巨噬细胞轴的免疫抑制作用及其作为治疗靶点的潜力。转录组分析显示，B7-H3在PD-L1低、非免疫反应性HGSOC肿瘤中高度表达，其表达与IFNγ特征负相关，这反映了肿瘤免疫反应性。在同基因小鼠模型中，肿瘤细胞中的B7-H3（Cd 276）敲除（KO）（但基质细胞中不敲除）抑制了肿瘤进展，M2巨噬细胞数量减少，IFNγ+ CD 8 + T细胞数量增加。在B7-H3 KO肿瘤细胞系中，CCL 2表达下调。CCL 2-CCR 2轴的抑制部分抵消了B7-H3抑制对M2巨噬细胞迁移和分化以及肿瘤进展的影响。在HGSOC患者中，B7-H3表达与CCL 2表达和M2巨噬细胞丰度呈正相关，B7-H3高表达肿瘤患者的肿瘤IFNγ+ CD 8 + T细胞数量少于B7-H3低表达肿瘤患者，预后较差。因此，肿瘤细胞中的B7-H3表达有助于CCL 2-CCR 2-M2巨噬细胞轴介导的免疫抑制和肿瘤进展。这些发现为免疫TME提供了新的见解，并有助于开发针对不利HGSOC表型的新治疗方法。
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.