Journal Article

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

Jun Hanaoka, Takuya Shiratori, Keiko Ueda, Yoko Kataoka, Keigo Okamoto, Atsuko Watanabe, Tomoaki Suzuki, Yo Kawaguchi, Yasuhiko Ohshio

2023

Overview

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. Nimesulide blocked the secretion of MCP‐1 and PGE2 from tumor cells, resulting in the depletion of M2 tumor‐associated macrophages (TAMs) in the tumor microenvironment (TME). Combination therapy of nimesulide with cisplatin considerably suppressed tumor growth in the LLC mouse model.

• Publisher: Wiley,John Wiley & Sons, Inc,John Wiley and Sons Inc
• Subject: Animals / Antibodies / Antitumor activity / Biomedical research / Cancer therapies / Cell adhesion & migration / Cell differentiation / Cell Line, Tumor / Chemotherapy / Cisplatin / Cisplatin - therapeutic use / Clinical trials / Dinoprostone / Dinoprostone - therapeutic use / Enzyme-linked immunosorbent assay / Flow cytometry / Leukocyte migration / Lung cancer / Lung Neoplasms / Lung Neoplasms - pathology / M2-like tumor-associated macrophages / Macrophages / Metastasis / Mice / Monocyte chemoattractant protein / Monocyte chemoattractant protein 1 / Monocytes / Nimesulide / Original / ORIGINAL ARTICLES / Phenotypes / Prostaglandin E2 / R&D / Recruitment / Research & development / Therapeutic targets / Tumor cell lines / Tumor cells / Tumor Microenvironment / Tumor Microenvironment - genetics / Tumor-Associated Macrophages / Tumor-Associated Macrophages - metabolism