Department of Immunology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran; Pediatric Cell and Gene Therapy Research Center, Gene, Cell & Tissue Research Institute, Tehran University of Medical Sciences, Tehran, Iran.
Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
Life Sci. 2022 Feb 1;290:120234. doi: 10.1016/j.lfs.2021.120234. Epub 2021 Dec 23.
As conventional therapeutics failed to provide satisfied outcomes against one of the most prevalent cancers, colorectal cancer (CRC), we purposed to implicate MicroRNA (miR)-34a, as a major tumor suppressor, to be delivered by tumor-derived exosomes (TEXs) and investigated its anti-tumor functions in-vivo.
TEXs were isolated from CT-26 cell line and loaded with miR-34a mimic. Then, mice bearing CRC were treated with miR-34a-enriched TEX (TEX-miR-34a) and then examined for the relative tumor-suppressive impacts of the TEX as well as its potential in promoting an anti-tumor immune response.
TEX-miR-34a significantly reduced tumor size and prolonged survival of mice bearing CRC. TEX-miR-34a was able to diminish gene expressions related to invasion, angiogenesis and immune evasion. It was also capable of inducing T cell polarization toward CD8+ T subsets among tumor-infiltrating lymphocytes, draining lymph nodes (DLNs) and spleen cells. Moreover, cytotoxic T cells were professionally induced in mice receiving TEX-miR-34a and the secretion of interleukin (IL)-6, IL-17A and tumor necrosis factor (TGF)-β was reduced in DLNs. However, the enhanced levels of interferon-γ were evaluated in DLN and spleen displaying the polarization of anti-tumor immune responses. Interestingly, mice receiving TEX alone showed a noticeable reduction in certain oncogenic gene expressions as well as IL-17A secretion in DLNs.
TEX-miR-34a demonstrated the potential to induce beneficial anti-tumor immune responses and TEXs, aside from the delivery function of miRNA, revealed certain anti-tumor beneficial characteristics which could introduce TEX-miR-34a as a promising approach in CRC combination therapies.
由于常规疗法未能为最常见的癌症之一——结直肠癌（CRC）提供满意的疗效，我们拟通过肿瘤来源的外泌体（TEXs）递送肿瘤抑制因子 MicroRNA（miR）-34a，并研究其在体内的抗肿瘤功能。
从 CT-26 细胞系中分离 TEXs 并负载 miR-34a 模拟物。然后，用富含 miR-34a 的 TEX（TEX-miR-34a）治疗携带 CRC 的小鼠，然后检查 TEX 的相对肿瘤抑制作用及其促进抗肿瘤免疫反应的潜力。
TEX-miR-34a 显著减小了携带 CRC 的小鼠的肿瘤大小并延长了其生存时间。TEX-miR-34a 能够降低与侵袭、血管生成和免疫逃逸相关的基因表达。它还能够诱导肿瘤浸润淋巴细胞、引流淋巴结（DLNs）和脾细胞中 T 细胞向 CD8+T 亚群极化。此外，在接受 TEX-miR-34a 的小鼠中专业诱导了细胞毒性 T 细胞，并且在 DLNs 中减少了白细胞介素（IL）-6、IL-17A 和肿瘤坏死因子（TGF）-β的分泌。然而，在 DLN 和脾中评估了增强的干扰素-γ水平，显示出抗肿瘤免疫反应的极化。有趣的是，单独接受 TEX 的小鼠在某些致癌基因表达以及 DLNs 中的 IL-17A 分泌方面也明显减少。
TEX-miR-34a 显示出诱导有益的抗肿瘤免疫反应的潜力，而除了 miRNA 的递送功能外，TEX 还显示出某些抗肿瘤的有益特征，这可能使 TEX-miR-34a 成为 CRC 联合治疗的一种有前途的方法。
