The anti-tumor effects of CT-26 derived exosomes enriched by MicroRNA-34a on murine model of colorectal cancer

• Published in: Life sciences (1973) 2022-02, Vol.290, p.120234-120234, Article 120234
• Main Authors: Hosseini, Maryam, Baghaei, Kaveh, Hajivalili, Mahsa, Zali, Mohammad Reza, Ebtekar, Masoumeh, Amani, Davar
• Format: Article
• Language: English
• Subjects: Angiogenesis; Animal models; Animals; Anti-tumor immune response; Anticancer properties; Antitumor activity; Cancer; Carcinogenesis - genetics; CD8 antigen; Cell Line, Tumor; Cell Proliferation - drug effects; Colorectal cancer; Colorectal carcinoma; Colorectal Neoplasms - genetics; Colorectal Neoplasms - metabolism; Colorectal Neoplasms - therapy; Cytotoxicity; Disease Models, Animal; Drug Delivery Systems - methods; Exosome; Exosomes; Exosomes - genetics; Exosomes - metabolism; Gene Expression - genetics; Gene Expression Regulation, Neoplastic - genetics; Immune response; Immune system; Immunotherapy; Interferon; Interleukin-17 - metabolism; Interleukins; Lymph nodes; Lymphocytes; Lymphocytes T; Lymphocytes, Tumor-Infiltrating - pathology; Mice; MicroRNAs; MicroRNAs - genetics; MicroRNAs - metabolism; miR-34a; miRNA; Polarization; Spleen; T cell; T-Lymphocytes, Cytotoxic - immunology; Tomography, X-Ray Computed - methods; Transforming Growth Factor beta - metabolism; Tumor suppressor genes; Tumor-infiltrating lymphocytes; γ-Interferon
• ISSN: 0024-3205; 1879-0631
• DOI: 10.1016/j.lfs.2021.120234

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. [Display omitted]