miR-22 gene therapy treats HCC by promoting anti-tumor immunity and enhancing metabolism

  • Mol Ther. 2023 May 4;S1525-0016(23)00253-8. doi: 10.1016/j.ymthe.2023.04.019.
Ying Hu  1 ,  Tahereh Setayesh  1 ,  Farzam Vaziri  1 ,  Xuesong Wu  2 ,  Samuel T Hwang  2 ,  Xin Chen  3 ,  Yu-Jui Yvonne Wan  4
Affiliations
  • 1. Department of Pathology and Laboratory Medicine, University of California Davis Health, Sacramento, CA, 95817, USA.
  • 2. Department of Dermatology, University of California Davis Healthy, Sacramento, CA, 95817, USA.
  • 3. Cancer Biology Program, University of Hawaii Cancer Center, Honolulu, HI, 96813, USA.
  • 4. Department of Pathology and Laboratory Medicine, University of California Davis Health, Sacramento, CA, 95817, USA. Electronic address: [email protected].
PMID: 37143325 DOI: 10.1016/j.ymthe.2023.04.019
Abstract

MicroRNA-22 (miR-22) can be induced by beneficial metabolites that have metabolic and immune effects, including retinoic acids, bile acids, vitamin D3, and short-chain fatty acids. The tumor suppressor effects of miR-22 have been suggested, but whether miR-22 treats orthotopic hepatocellular carcinoma (HCC) is not established. The role of miR-22 in regulating tumor immunity is poorly understood. Our data showed that miR-22 delivered by adeno-associated virus serotype 8 (AAV8) effectively treated HCC. Compared with FDA-approved Lenvatinib, miR-22 produced better survival outcomes without noticeable toxicity. miR-22 silenced hypoxia-inducible factor 1 (HIF1α) and enhanced retinoic acid signaling in both hepatocytes and T cells. Moreover, miR-22 treatment improved metabolism and reduced inflammation. In the liver, miR-22 reduced the abundance of IL17-producing T cells and inhibited IL17 signaling by reducing the occupancy of HIF1α in the Rorc and Il17a genes. Conversely, increasing IL17 signaling ameliorated the anti-HCC of miR-22. Additionally, miR-22 expanded cytotoxic T cells and reduced regulatory T cells (Treg). Moreover, depleting cytotoxic T cells also abolished the anti-HCC effects of miR-22. In patients, miR-22 high human HCC had up-regulated metabolic pathways and reduced IL17 pro-inflammatory signaling compared with miR-22 low HCC. Together, miR-22 gene therapy can be a novel option for HCC treatment.

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