肿瘤相关巨噬细胞的消耗抑制肺癌生长并增强顺铂的抗肿瘤作用,Cancer Science

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肿瘤相关巨噬细胞的消耗抑制肺癌生长并增强顺铂的抗肿瘤作用
Cancer Science ( IF 4.5 ) Pub Date : 2022-11-21 , DOI: 10.1111/cas.15671
Yo Kawaguchi ₁ , Yasuhiko Ohshio ₁ , Atsuko Watanabe ₁ , Takuya Shiratori ₁ , Keigo Okamoto ₁ , Keiko Ueda ₁ , Yoko Kataoka ₁ , Tomoaki Suzuki ₂ , Jun Hanaoka ₁

Affiliation

在肺癌中，肿瘤相关巨噬细胞 (TAM)，尤其是 M2 样 TAM，代表了肿瘤微环境 (TME) 中的主要肿瘤进展成分。因此，M2 样 TAM 可作为治疗靶点。本研究的目的是研究 TME 中 M2 样 TAM 耗竭对肺癌肿瘤生长和化疗反应的影响。通过 ELISA 评估肺癌细胞系 A549 和 LLC 上清液中分泌的单核细胞趋化蛋白 (MCP-1) 和前列腺素 E2 (PGE2) 的水平。进行细胞迁移测定以评估巨噬细胞系 THP-1 和 J774-1 细胞的募集能力。通过流式细胞术评估巨噬细胞的分化。进行免疫组织化学染色以观察小鼠移植肺癌中的 M2 样 TAM。我们使用 COX-2 抑制剂尼美舒利抑制 MCP-1 和 PGE2 的分泌，从而促进巨噬细胞迁移和 M2 样分化。尼美舒利治疗降低了肺癌细胞 MCP-1 和 PGE2 的分泌。尼美舒利治疗通过阻断 MCP-1 抑制巨噬细胞的迁移。肺癌上清液诱导巨噬细胞向 M2 样表型分化，尼美舒利治疗通过阻断 MCP-1 和 PGE2 抑制 M2 样分化。在肺癌小鼠模型中，尼美舒利治疗耗尽了 TME 中的 M2 样 TAM，并增强了顺铂的肿瘤抑制作用。

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Depletion of tumor-associated macrophages inhibits lung cancer growth and enhances the antitumor effect of cisplatin

In lung cancer, tumor-associated macrophages (TAMs), especially M2-like TAMs, represent the main tumor progression components in the tumor microenvironment (TME). Therefore, M2-like TAMs may serve as a therapeutic target. The purpose of this study was to investigate the effect of M2-like TAM depletion in the TME on tumor growth and chemotherapy response in lung cancer. The levels of secreted monocyte chemoattractant protein (MCP-1) and prostaglandin E2 (PGE2) in the supernatants of lung cancer cell lines A549 and LLC were evaluated via ELISA. Cell migration assays were performed to assess the recruitment ability of macrophage cell lines THP-1 and J774-1 cells. Differentiation of macrophages was assessed via flow cytometry. Immunohistochemical staining was performed to visualize M2-like TAMs in transplanted lung cancer in mouse. We used the COX-2 inhibitor nimesulide to inhibit the secretion of MCP-1 and PGE2, which promotes macrophage migration and M2-like differentiation. Nimesulide treatment decreased the secretion of MCP-1 and PGE2 from lung cancer cells. Nimesulide treatment suppressed the migration of macrophages by blocking MCP-1. Lung cancer supernatant induced the differentiation of macrophages toward the M2-like phenotype, and nimesulide treatment inhibited M2-like differentiation by blocking MCP-1 and PGE2. In the lung cancer mouse model, treatment with nimesulide depleted M2-like TAMs in the TME and enhanced the tumor inhibitory effect of cisplatin. Our results indicated that blocking the secretion of MCP-1 and PGE2 from tumor cells depleted M2-like TAMs in the TME and the combination therapy with cisplatin considerably suppressed tumor growth in the LLC mouse model.

更新日期：2022-11-21

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