Exosome miR-27a-3p secreted from adipocytes targets ICOS to promote antitumor immunity in lung adenocarcinoma
Exosome miR-27a-3p secreted from adipocytes targets ICOS to promote antitumor immunity in lung adenocarcinoma
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脂肪细胞分泌的外泌体 miR-27a-3p 靶向 ICOS 促进肺腺癌的抗肿瘤免疫
DOI：
10.1111/1759-7714.13411
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发表时间：
2020-03-25
期刊：
影响因子：
2.9
通讯作者：
Huang, Dingzhi
中科院分区：
文献类型：
--
作者：
Fan, Xuehan;Wang, Jingya;Huang, Dingzhi
背景免疫治疗的临床获益仅限于一小部分癌症患者。在多种癌症中使用免疫检查点抑制剂的几项临床试验显示，肥胖患者的情况有所改善。方法采用生物信息学分析方法，寻找与体重指数（BMI）相关的免疫微环境相关基因。采用Western blot、免疫组化、实时荧光定量聚合酶链反应（RT-qPCR）和流式细胞术检测肿瘤组织中ICOS的表达。RT-qPCR检测miR-27 a-3 p的表达。通过双荧光素酶报告基因分析证实miR-27 a-3 p与ICOS之间的相互作用。采用ELISA和流式细胞术检测T细胞增殖和IFN-γ分泌功能。结果肥胖肺腺癌患者免疫微环境相关基因ICOS表达显著上调。miR-27 a-3 p与ICOS呈负相关，并抑制ICOS的表达。结论脂肪细胞来源的exo-miR-27 a-3 p可以抑制ICOS + T细胞增殖和IFN-γ分泌，从而改变肿瘤微环境。脂肪组织来源的外泌体中miR-27 a-3 p的下调引起的ICOS+ T细胞功能的上调是肥胖LUAD患者中免疫疗法改善疗效的潜在机制之一。
Background The clinical benefit of immunotherapy has been limited to a small subset of patients with cancer. Several clinical trials with immune checkpoint inhibitors in multiple cancers have shown some improvement in obese patients. However, how obesity regulates the immune microenvironment remains unclear.Methods Bioinformatic analysis was used to discover immune microenvironmental-related genes associated with body mass index (BMI). The expression of ICOS in tumor tissues was detected using western blot, immunohistochemistry, quantitative real-time polymerase chain reaction (RT-qPCR) and flow cytometry. RT-qPCR was used to measure the expression of miR-27a-3p. The interaction between miR-27a-3p and ICOS was confirmed by dual-luciferase reporter assay. Functional testing of T cells based on proliferation and interferon (IFN)-gamma secretion was performed using ELISA and flow cytometry.Results ICOS, an immune microenvironment-related gene, was significantly upregulated in obese patients with lung adenocarcinoma (LUAD). MiR-27a-3p showed a negative correlation with ICOS and suppressed the expression of ICOS. We determined that dipocyte-derived exo-miR-27a-3p could alter the tumor microenvironment by inhibiting ICOS+ T cell proliferation and IFN-gamma secretion in vitro.Conclusions Adipocyte-derived exo-miR-27a-3p can inhibit ICOS+ T cell proliferation and IFN-gamma secretion. The upregulation of ICOS+ T cell functions caused by the downregulation of miR-27a-3p in adipose tissue derived exosomes is one of the potential mechanisms for the improved efficacy of immunotherapy in obese LUAD patients.