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4-甲基伞形酮介导的 M1 巨噬细胞极化与小鼠肝癌侵袭性降低相关。

4-methylumbelliferone-mediated polarization of M1 macrophages correlate with decreased hepatocellular carcinoma aggressiveness in mice.

机构信息

Gene Therapy Laboratory, Facultad de Ciencias Biomédicas, Instituto de Investigaciones en Medicina Traslacional, CONICET-Universidad Austral, Av. Presidente Perón 1500 (B1629ODT) Derqui-Pilar, Buenos Aires, Argentina.

Department of Medicine, Universitätsklinikum Knappschaftskrankenhaus Bochum, Ruhr-Universität Bochum, Bochum, Germany.

出版信息

Sci Rep. 2021 Mar 18;11(1):6310. doi: 10.1038/s41598-021-85491-0.

DOI:10.1038/s41598-021-85491-0
PMID:33737571
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7973733/
Abstract

Hepatocellular carcinoma (HCC) arises in the setting of advanced liver fibrosis, a dynamic and complex inflammatory disease. The tumor microenvironment (TME) is a mixture of cellular components including cancer cells, cancer stem cells (CSCs), tumor-associated macrophages (TAM), and dendritic cells (DCs), which might drive to tumor progression and resistance to therapies. In this work, we study the effects of 4-methylumbelliferone (4Mu) on TME and how this change could be exploited to promote a potent immune response against HCC. First, we observed that 4Mu therapy induced a switch of hepatic macrophages (Mϕ) towards an M1 type profile, and HCC cells (Hepa129 cells) exposed to conditioned medium (CM) derived from Mϕ treated with 4Mu showed reduced expression of several CSCs markers and aggressiveness. HCC cells incubated with CM derived from Mϕ treated with 4Mu grew in immunosuppressed mice while presented delayed tumor progression in immunocompetent mice. HCC cells treated with 4Mu were more susceptible to phagocytosis by DCs, and when DCs were pulsed with HCC cells previously treated with 4Mu displayed a potent antitumoral effect in therapeutic vaccination protocols. In conclusion, 4Mu has the ability to modulate TME into a less hostile milieu and to potentiate immunotherapeutic strategies against HCC.

摘要

肝细胞癌 (HCC) 发生在晚期肝纤维化的背景下，这是一种动态且复杂的炎症性疾病。肿瘤微环境 (TME) 是一种细胞成分的混合物，包括癌细胞、癌症干细胞 (CSC)、肿瘤相关巨噬细胞 (TAM) 和树突状细胞 (DC)，这些成分可能推动肿瘤进展和对治疗的耐药性。在这项工作中，我们研究了 4-甲基伞形酮 (4Mu) 对 TME 的影响，以及这种变化如何被利用来促进针对 HCC 的有效免疫反应。首先，我们观察到 4Mu 治疗诱导肝巨噬细胞 (Mϕ) 向 M1 型表型转变，并且暴露于由用 4Mu 处理的 Mϕ 产生的条件培养基 (CM) 的 HCC 细胞 (Hepa129 细胞) 显示出几种 CSC 标志物的表达减少和侵袭性降低。在免疫抑制小鼠中，用 CM 孵育的 HCC 细胞来自用 4Mu 处理的 Mϕ 生长，而在免疫活性小鼠中则表现出肿瘤进展延迟。用 4Mu 处理的 HCC 细胞更容易被 DC 吞噬，并且当用先前用 4Mu 处理的 HCC 细胞脉冲处理的 DC 时，在治疗性疫苗接种方案中显示出强大的抗肿瘤作用。总之，4Mu 具有调节 TME 进入不那么敌对环境的能力，并增强针对 HCC 的免疫治疗策略。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/be9d/7973733/c43de93222bd/41598_2021_85491_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/be9d/7973733/e78e6c4d837e/41598_2021_85491_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/be9d/7973733/dc053aacfc81/41598_2021_85491_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/be9d/7973733/cc4bbb335de5/41598_2021_85491_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/be9d/7973733/f2e36825eefc/41598_2021_85491_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/be9d/7973733/c43de93222bd/41598_2021_85491_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/be9d/7973733/e78e6c4d837e/41598_2021_85491_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/be9d/7973733/dc053aacfc81/41598_2021_85491_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/be9d/7973733/cc4bbb335de5/41598_2021_85491_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/be9d/7973733/f2e36825eefc/41598_2021_85491_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/be9d/7973733/c43de93222bd/41598_2021_85491_Fig5_HTML.jpg

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