Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai, China.
Biotherapy Research Center, Fudan University, Shanghai, China.
Int J Cancer. 2017 Nov 15;141(10):2082-2092. doi: 10.1002/ijc.30912. Epub 2017 Aug 18.
MiR-15a/16, a miRNA cluster located at chromosome 13q14, has been reported to act as an immune regulator in inflammatory disorders besides its aberrant expression in cancers. However, little is known about its regulation in tumor-infiltrating immune cells. In our study, using an orthotropic GL261 mouse glioma model, we found that miR-15a/16 deficiency in host inhibited tumor growth and prolonged mice survival, which might be associated with the accumulation of tumor-infiltrating CD8+ T cells. More importantly, tumor-infiltrating CD8+ T cells without miR-15a/16 showed lower expression of PD-1, Tim-3 and LAG-3, and stronger secretion of IFN-γ, IL-2 and TNF-α than WT tumor-infiltrating CD8+ T cells. Also, our in vitro experiments further confirmed that miR-15a/16 CD8+ T displayed higher active phenotypes, more cytokines secretion and faster expansion, compared to WT CD8+ T cells. Mechanismly, mTOR was identified as a target gene of miR-15a/16 to negatively regulate the activation of CD8+ T cells. Taken together, these data suggest that miR-15a/16 deficiency resists the exhaustion and maintains the activation of glioma-infiltrating CD8+ T cells to alleviate glioma progression via targeting mTOR. Our findings provide evidence for the potential immunotherapy through targeting miR-15a/16 in tumor-infiltrating immune cells.
miR-15a/16，位于染色体 13q14 上的 miRNA 簇，除了在癌症中异常表达外，还被报道在炎症性疾病中作为免疫调节剂发挥作用。然而，miR-15a/16 在肿瘤浸润免疫细胞中的调控作用知之甚少。在我们的研究中，使用原位 GL261 小鼠胶质瘤模型，我们发现宿主中 miR-15a/16 的缺失抑制了肿瘤生长并延长了小鼠的存活期，这可能与肿瘤浸润 CD8+T 细胞的积累有关。更重要的是，缺乏 miR-15a/16 的肿瘤浸润 CD8+T 细胞表现出较低的 PD-1、Tim-3 和 LAG-3 表达，以及更强的 IFN-γ、IL-2 和 TNF-α 分泌，而 WT 肿瘤浸润 CD8+T 细胞则没有。此外，我们的体外实验进一步证实，与 WT CD8+T 细胞相比，miR-15a/16 CD8+T 细胞表现出更高的激活表型、更多细胞因子分泌和更快的扩增。机制上，mTOR 被鉴定为 miR-15a/16 的靶基因，负调控 CD8+T 细胞的激活。综上所述，这些数据表明，miR-15a/16 的缺失通过靶向 mTOR 抵抗耗尽并维持胶质瘤浸润 CD8+T 细胞的激活，从而减轻胶质瘤的进展。我们的研究结果为通过靶向肿瘤浸润免疫细胞中的 miR-15a/16 进行潜在的免疫治疗提供了证据。
