Abstract
Tumor-associated macrophages (TAMs) facilitate cancer progression by promoting tumor invasion, angiogenesis, metastasis, inflammatory responses, and immunosuppression. Folate receptor β (FRβ) is overexpressed in TAMs. However, the clinical significance of FRβ-positive macrophages in lung cancer remains poorly understood. In this study, we verified that FRβ overexpression in lung cancer TAMs was associated with poor prognosis. We utilized a folate-modified lipoplex comprising a folate-modified liposome (F-PLP) delivering a BIM-S plasmid to target both lung cancer cells and FRβ-positive macrophages in the tumor microenvironment. Transfection of LL/2 cells and MH-S cells with F-PLP/pBIM induced cell apoptosis. Injection of F-PLP/pBIM into LL/2 and A549 lung cancer models significantly depleted FRβ-positive macrophages and reduced tumor growth. Treatment of tumor-bearing mice with F-PLP/pBIM significantly inhibited tumor growth in vivo by inducing tumor cell and macrophage apoptosis, reducing tumor proliferation, and inhibiting tumor angiogenesis. In addition, a preliminary safety evaluation demonstrated a good safety profile of F-PLP/pBIM as a gene therapy administered intravenously. This work describes a novel application of lipoplexes in lung cancer targeted therapy that influences the tumor microenvironment by targeting TAMs.
Highlights
Lung cancer is the most commonly diagnosed cancer and is the leading cause of cancer deaths among males and females worldwide.[1]
We found that FRα could not be used as a predictor of lung cancer prognosis (p = 0.356, 95% CI 0.788–1.938), whereas Folate receptor β (FRβ) could be used as an independent predictor of lung cancer prognosis (p = 0.000, 95% CI 1.794–4.913)
We found that high FRβ expression was an independent predictor of lung adenocarcinoma prognosis (p = 0.003, 95% CI 1.491–6.536) and an independent predictor of lung squamous cell carcinoma prognosis (p = 0.002, 95% CI 1.793–12.465)
Summary
Lung cancer is the most commonly diagnosed cancer and is the leading cause of cancer deaths among males and females worldwide.[1]. Tumor-associated macrophages (TAMs), which are local tumor macrophages, account for the majority of leukocytes in the tumor microenvironment. Once mononuclear macrophages are recruited to the tumor microenvironment, they polarize into M1 or M2 macrophages affected by various factors. M2 macrophages promote tumor invasion, metastasis, and inflammatory responses. TAMs in the tumor microenvironment tend to adopt the anti-inflammatory M2-like phenotype.[4] TAMs participate in tumor invasion, growth, angiogenesis, metastasis, and immunosuppression and in neovascularization and matrix degradation.[5] Strategies that target
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