Immune Surveillance Vs. Immune Escape: Strategic Release of Exosomal Micrornas and Gapdh for Immunoediting in Hepatocellular Carcinoma

The existence of tumor-derived factors in the peripheral blood is one of potential mechanisms for development and recurrence of hepatocellular carcinoma (HCC). Exosomes are one of tumor-derived microvesicles and our previous study demonstrated the impact of circulating exosomes on HCC development. Thanks to the present grant support, we have successfully identified HCC-relative microRNAs including miR-92b and miR-4669 in experimental and clinical HCC model/patients.Briefly, Hep3B cells overexpressing miR-92b released exosomes in the culture medium, which contain higher level of miR-92b. Therefore, released exosomes may transfer HCC-relative microRNAs to neighboring cells such as infiltrating natural killer (NK) cells in tumor microenvironment. The overexpression of miR-92b in primary NK cells significantly downregulated CD69, which plays a crucial role in NK cell functions, resulting in the loss of NK cell cytotoxicity. In addition, the elevation of serum exosomal miR-4669 was confirmed as one of risk factors for HCC recurrence after living donor liver transplantation (LDLT) and our pilot data revealed the impact of miR-4669 on HCC development. Besides, we have demonstrated the impact of extracellular glyceraldehyde-3-phosphate dehydrogenase (GAPDH) on immunosuppressive M2 macrophage polarization. Recent studies demonstrated the overexpression of GAPDH in a variety of cancer types, suggesting that GAPDH is potentially required for the cancer cell growth and tumor formation. Taken together, we speculate that HCC-derived exosomal microRNAs and GAPDH may edit not only tumor cell biology but also host immune system for creation of immunosuppressive tumor microenvironment, resulting in the favorable condition for cancer cell growth and tumor formation.In this project, we will explore the effect of miR-92b, miR-4669 and GAPDH on tumor cell biology and on tumor immune surveillance (1st year). We will mimic LDLT for HCC and explore the synergistic impact of miR-92b, miR-4669 and GAPDH on HCC development and recurrence after surgical resection of HCC with immunosuppressive treatment (2nd year). Finally, we will explore the therapeutic impact of GW4869, an inhibitor of exosome biogenesis/release, on HCC development and recurrence (3rd year). We expect to gather solid evidences to demonstrate the mechanisms of tumor development and immunoediting from immune surveillance to immune escape by strategic release of HCC-relative microRNAs and GAPDH in HCC.

Project ID:PC10708-0987
External Project ID:MOST107-2320-B182-032