肿瘤细胞治疗研究
英文原题：Inhibition of osteosarcoma lung metastases by β-glucan and CD40 agonist is mediated by activation of macrophages and NK cells.
我们的研究结果表明β-葡聚糖对OS肺肿瘤负荷具有抗肿瘤活性，β-葡聚糖与CD40a联合使用可增强治疗活性，且该活性由先天免疫（巨噬细胞和NK细胞）的激活所介导。
骨肉瘤（OS）肺转移仍然是一个重大的治疗挑战。先天免疫激活是一种有前景的治疗方法。先天免疫激动剂可以调节肿瘤免疫微环境并改善治疗反应。
使用K7M3-luc OS细胞构建的实验性同基因OS肺转移BALB/c小鼠模型，我们评估了酵母来源颗粒状β-葡聚糖在预防和治疗环境下的抗肿瘤效果。随后，我们在两种不同的免疫健全OS肺肿瘤负荷小鼠模型中评估了CD40激动剂（CD40a）联合β-葡聚糖是否能够提高治疗反应。
在预处理设置中，接受OS细胞输注前用β-葡聚糖处理的小鼠，肺部肿瘤负荷显著减少，生存期延长。β-葡聚糖预处理阻止了肿瘤细胞在肺部的种植。在荷瘤小鼠中，β-葡聚糖治疗显著抑制了肿瘤生长并延长了总生存期。β-葡聚糖治疗增加了肺部活化的促炎M1样巨噬细胞和分泌干扰素-γ和颗粒酶B的自然杀伤（NK）细胞。耗竭研究表明，β-葡聚糖的抗肿瘤作用依赖于巨噬细胞和NK细胞。此外，β-葡聚糖治疗还诱导了骨髓中的髓系生成。当与CD40a联合使用时，β-葡聚糖的治疗效益进一步增强。与单药治疗相比，联合治疗显著增加了活化巨噬细胞（包括分泌肿瘤坏死因子-α的巨噬细胞）和NK细胞向肺部的浸润。肺组织的bulk RNA测序显示，联合治疗组表现出抗肿瘤先天免疫通路的增强激活。
BACKGROUND: Osteosarcoma (OS) lung metastases remain a significant therapeutic challenge. Innate immune activation is a promising therapeutic approach. Innate immune agonists can modulate the tumor immune microenvironment and improve therapeutic response. METHODS: Using an experimental syngeneic OS lung metastasis BALB/c mouse model with K7M3-luc OS cells, we evaluated the antitumor effects of yeast-derived particulate β-glucan in prevention and therapeutic settings. We then assessed whether the CD40 agonist (CD40a) in combination with β-glucan increased therapeutic response in two different immune-competent mouse models of OS lung tumor burden. RESULTS: In the pretreatment settings, mice treated with β-glucan prior to OS cell infusion developed significantly fewer lung tumor burdens and had increased survival. Pretreatment with β-glucan prevented tumor cell seeding in the lungs. In tumor-bearing mice, β-glucan treatment significantly suppressed tumor growth and prolonged overall survival. β-glucan treatment increased activated pro-inflammatory M1-like macrophages and natural killer (NK) cells secreting interferon-γ and granzyme B in the lungs. Depletion studies showed that the antitumor effect of β-glucan was dependent on macrophages and NK cells. Additionally, β-glucan treatment also induced myelopoiesis in the bone marrow. The therapeutic benefit of β-glucan was further augmented when combined with CD40a. Combination therapy significantly increased the infiltration of activated macrophages, including tumor necrosis factor-α secreting macrophages, and NK cells into the lungs compared with monotherapy. Bulk RNA sequencing of lung tissue revealed that the combination treatment group exhibited enhanced activation of antitumor innate immune pathways. CONCLUSIONS: Collectively, our findings demonstrate the antitumor activity of β-glucan against OS lung tumor burden, that combining β-glucan and CD40a increases therapeutic activity, and that this activity is mediated by activation of innate immunity (macrophages and NK cells).
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