Cellular cross-talk within the tumor microenvironment (TME) by exosomes is known to promote tumor progression. Tumor promoting macrophages with an M2 phenotype are suppressors of anti-tumor immunity. However, the impact of tumor-derived exosomes in modulating macrophage polarization in the lung TME is largely unknown. Herein, we investigated if lung tumor-derived exosomes alter transcriptional and bioenergetic signatures of M0 macrophages and polarize them to an M2 phenotype. The concentration of exosomes produced by p53 null H358 lung tumor cells was significantly reduced compared to A549 (p53 wild-type) lung tumor cells, consistent with p53-mediated regulation of exosome production. In co-culture studies, M0 macrophages internalized tumor-derived exosomes, and differentiated into M2 phenotype. Importantly, we demonstrate that tumor-derived exosomes enhance the oxygen consumption rate of macrophages, altering their bioenergetic state consistent with that of M2 macrophages. In vitro co-cultures of M0 macrophages with H358 exosomes demonstrated that exosome-induced M2 polarization may be p53 independent. Murine bone marrow cells and bone marrow-derived myeloid-derived suppressor cells (MDSCs) co-cultured with lewis lung carcinoma (LLC)-derived exosomes differentiated to M2 macrophages. Collectively, these studies provide evidence for a novel role for lung tumor-exosomes in M2 macrophage polarization, which then offers new therapeutic targets for immunotherapy of lung cancer.

中文翻译：

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肺肿瘤细胞衍生的外泌体促进 M2 巨噬细胞极化。

已知外泌体在肿瘤微环境 (TME) 内的细胞串扰会促进肿瘤进展。具有 M2 表型的肿瘤促进巨噬细胞是抗肿瘤免疫的抑制因子。然而，肿瘤来源的外泌体在调节肺 TME 中巨噬细胞极化方面的影响在很大程度上是未知的。在这里，我们研究了肺肿瘤衍生的外泌体是否会改变 M0 巨噬细胞的转录和生物能量特征并将它们极化为 M2 表型。与 A549（p53 野生型）肺肿瘤细胞相比，p53 无效 H358 肺肿瘤细胞产生的外泌体浓度显着降低，这与 p53 介导的外泌体产生调节一致。在共培养研究中，M0 巨噬细胞内化肿瘤来源的外泌体，并分化为 M2 表型。重要的，我们证明了肿瘤来源的外泌体提高了巨噬细胞的耗氧率，改变了它们与 M2 巨噬细胞一致的生物能量状态。M0 巨噬细胞与 H358 外泌体的体外共培养表明，外泌体诱导的 M2 极化可能与 p53 无关。小鼠骨髓细胞和骨髓来源的骨髓来源的抑制细胞 (MDSCs) 与刘易斯肺癌 (LLC) 来源的外泌体共培养，分化为 M2 巨噬细胞。总的来说，这些研究为肺肿瘤外泌体在 M2 巨噬细胞极化中的新作用提供了证据，从而为肺癌的免疫治疗提供了新的治疗靶点。M0 巨噬细胞与 H358 外泌体的体外共培养表明，外泌体诱导的 M2 极化可能与 p53 无关。小鼠骨髓细胞和骨髓来源的骨髓来源的抑制细胞 (MDSCs) 与刘易斯肺癌 (LLC) 来源的外泌体共培养，分化为 M2 巨噬细胞。总的来说，这些研究为肺肿瘤外泌体在 M2 巨噬细胞极化中的新作用提供了证据，从而为肺癌的免疫治疗提供了新的治疗靶点。M0 巨噬细胞与 H358 外泌体的体外共培养表明，外泌体诱导的 M2 极化可能与 p53 无关。小鼠骨髓细胞和骨髓来源的骨髓来源的抑制细胞 (MDSCs) 与刘易斯肺癌 (LLC) 来源的外泌体共培养，分化为 M2 巨噬细胞。总的来说，这些研究为肺肿瘤外泌体在 M2 巨噬细胞极化中的新作用提供了证据，从而为肺癌的免疫治疗提供了新的治疗靶点。