Part:BBa_K4469007

miRNA 26a

miRNA-26a is shown to enhance T infiltration through suppression of the interleukin-6(IL-6) signaling pathway. IL-6 is one of the major cytokines in tumor microenvironment that has been actively involved in the progression of various tumors through different pathways. Studies have found that a much higher level of IL-6 is found in metastatic cell lines from rat HCC, and a much more significant increase of serum IL-6 level was found in patients with HCC compared to other liver diseases such as cirrhosis (Johnson et al, 2012).

In general, IL-6 blockade therapy would enhance CD8+ T cell recruitment and dendritic cells tumor-associated antigens presentation to boost the anti-tumor immunity (Tsukamoto et al, 2017). To highlight the importance of IL-6 in our project, it is noted that increased IL-6 secretion by tumor cells would activate the STAT3 pathway in CD4+ T cells and myeloid cells, and stimulate the differentiation of CD4+ T cells into IL-4-producing Th2-like cells (ibid) rather than IFN-𝛾-producing effector Th1 cells. IFN-𝛾 was also proved to boost the production of the chemokines CXCL9 and CXCL10 by tumor-localized myeloid cells to facilitate the migration of CXCR3+ NK and CD8+ T cells towards the tumor (Bergamaschi et al, 2020). Therefore, using the miRNA-26a which can suppress the IL-6 expression in liver tumor cells (Yang et al, 2013), would help establish a positive feedback loop and lower the impact of the tumor environment for CAR-T infiltration. Moreover, it is known that the IL-6/STAT3 pathway facilitates immunosuppression through downregulation of human leukocyte antigen on dendritic cells.

Reference

Bergamaschi, C., Pandit, H., Nagy, B. A., Stellas, D., Jensen, S. M., Bear, J., Cam, M., Valentin, A., Fox, B. A., Felber, B. K., & Pavlakis, G. N. (2020). Heterodimeric IL-15 delays tumor growth and promotes intratumoral CTL and dendritic cell accumulation by a cytokine network involving XCL1, IFN-γ, CXCL9 and CXCL10. Journal for ImmunoTherapy of Cancer, 8(1). https://doi.org/10.1136/jitc-2020-000599

Johnson, C., Han, Y., Hughart, N., McCarra, J., Alpini, G., & Meng, F. (2012). Interleukin-6 and its receptor, key players in hepatobiliary inflammation and cancer. Psychologia Latina, 1(1), 58-70.

Tsukamoto, H., Fujieda, K., Senju, S., Ikeda, T., Oshiumi, H., & Nishimura, Y. (2017). Immune-suppressive effects of interleukin-6 on T-cell-mediated anti-tumor immunity. Cancer Science, 109(3), 523–530. https://doi.org/10.1111/cas.13433

Yang, X., Liang, L., Zhang, X.-F., Jia, H.-L., Qin, Y., Zhu, X.-C., Gao, X.-M., Qiao, P., Zheng, Y., Sheng, Y.-Y., Wei, J.-W., Zhou, H.-J., Ren, N., Ye, Q.-H., Dong, Q.-Z., & Qin, L.-X. (2013). MicroRNA-26A suppresses tumor growth and metastasis of human hepatocellular carcinoma by targeting interleukin-6-stat3 pathway. Hepatology, 58(1), 158–170. https://doi.org/10.1002/hep.26305

Sequence and Features

Assembly Compatibility:

• 10
  COMPATIBLE WITH RFC[10]
• 12
  COMPATIBLE WITH RFC[12]
• 21
  COMPATIBLE WITH RFC[21]
• 23
  COMPATIBLE WITH RFC[23]
• 25
  COMPATIBLE WITH RFC[25]
• 1000
  COMPATIBLE WITH RFC[1000]