Suppressing miR-21 activity in tumor-associated macrophages promotes an antitumor immune response
Suppressing miR-21 activity in tumor-associated macrophages promotes an antitumor immune response
复制标题
抑制肿瘤相关巨噬细胞中的miR-21活性促进抗肿瘤免疫反应
DOI：
10.1172/jci127125
复制
发表时间：
2019-12-02
影响因子：
15.9
通讯作者：
Suarez, Yajaira
中科院分区：
文献类型：
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作者：
Sahraei, Mahnaz;Chaube, Balkrishna;Suarez, Yajaira
microRNA-21 (miR-21) 是实体瘤中最常见上调的 miRNA。这种与癌症相关的 microRNA (oncomiR) 在癌发生的各个阶段调节与肿瘤发病机制相关的各种下游效应子。在本研究中，我们分析了 miR-21 在肿瘤微环境的非癌细胞中的功能，以进一步评估其对肿瘤进展的贡献。我们报告说，肿瘤免疫浸润细胞，特别是巨噬细胞中的 miR-21 表达，负责促进肿瘤生长。肿瘤相关巨噬细胞 (TAM) 中 miR-21 表达的缺失导致其转录调控网络的整体重新布线，偏向于促炎性血管抑制表型。这促进了抗肿瘤免疫反应，其特征是通过诱导细胞因子和趋化因子（包括 IL-12 和 C-X-C 基序趋化因子 10），巨噬细胞介导的细胞毒性 T 细胞反应得到改善。这些效应转化为减少肿瘤新生血管形成和诱导肿瘤细胞死亡，从而减少肿瘤生长。此外，使用载体肽 pH（低）插入肽，我们能够靶向 TAM 中的 miR-21，即使在癌细胞中 miR-21 表达不足的条件下，也能减少肿瘤生长。因此，TAM 中的 miR-21 抑制诱导血管抑制和免疫刺激激活，具有潜在的治疗意义。
microRNA-21 (miR-21) is the most commonly upregulated miRNA in solid tumors. This cancer-associated microRNA (oncomiR) regulates various downstream effectors associated with tumor pathogenesis during all stages of carcinogenesis. In this study, we analyzed the function of miR-21 in noncancer cells of the tumor microenvironment to further evaluate its contribution to tumor progression. We report that the expression of miR-21 in cells of the tumor immune infiltrate, and in particular in macrophages, was responsible for promoting tumor growth. Absence of miR-21 expression in tumor-associated macrophages (TAMs), caused a global rewiring of their transcriptional regulatory network that was skewed toward a proinflammatory angiostatic phenotype. This promoted an antitumoral immune response characterized by a macrophage-mediated improvement of cytotoxic T-cell responses through the induction of cytokines and chemokines, including IL-12 and C-X-C motif chemokine 10. These effects translated to a reduction in tumor neovascularization and an induction of tumor cell death that led to decreased tumor growth. Additionally, using the carrier peptide pH (low) insertion peptide, we were able to target miR-21 in TAMs, which decreased tumor growth even under conditions where miR-21 expression was deficient in cancer cells. Consequently, miR-21 inhibition in TAMs induced an angiostatic and immunostimulatory activation with potential therapeutic implications.