MicroRNA-15a/16-1 Prevents Hepatocellular Carcinoma by Disrupting the Communication Between Kupffer Cells and Regulatory T Cells

Ningning Liu; Ching Wen Chang; Clifford J Steer; Xin Wei Wang; Guisheng Song

doi:10.1053/j.gastro.2021.10.015

MicroRNA-15a/16-1 Prevents Hepatocellular Carcinoma by Disrupting the Communication Between Kupffer Cells and Regulatory T Cells

Gastroenterology. 2022 Feb;162(2):575-589. doi: 10.1053/j.gastro.2021.10.015. Epub 2021 Oct 19.

Authors

Ningning Liu¹, Ching Wen Chang², Clifford J Steer³, Xin Wei Wang², Guisheng Song⁴

Affiliations

¹ Department of Medicine, University of Minnesota Medical School, Minneapolis, Minnesota.
² Center for Cancer Research, National Cancer Institute, Bethesda, Maryland.
³ Department of Medicine, University of Minnesota Medical School, Minneapolis, Minnesota; Department of Genetics, Cell Biology and Development, University of Minnesota, Minneapolis, Minnesota.
⁴ Department of Medicine, University of Minnesota Medical School, Minneapolis, Minnesota; Department of Genetics, Cell Biology and Development, University of Minnesota, Minneapolis, Minnesota. Electronic address: gsong@umn.edu.

PMID: 34678217
DOI: 10.1053/j.gastro.2021.10.015

Abstract

Background & aims: Hepatocellular carcinoma (HCC) is characterized by intratumoral accumulation of regulatory T cells (Tregs), which suppresses antitumor immunity. This study was designed to investigate how microRNAs regulate immunosuppression in HCC.

Methods: FVB/NJ mice were hydrodynamically injected with AKT/Ras or c-Myc and Sleeping Beauty transposon to induce HCC. The Sleeping Beauty system was used to deliver microRNA-15a/16-1 into livers of mice. Flow cytometry and immunostaining were used to determine changes in the immune system.

Results: Hydrodynamic injection of AKT/Ras or c-Myc into mice resulted in hepatic enrichment of Tregs and reduced cytotoxic T cells (CTLs) and HCC development. HCC impaired microRNA-15a/16-1 biogenesis in Kupffer cells (KCs) of AKT/Ras and c-Myc mice. Hydrodynamic injection of microRNA-15a/16-1 fully prevented HCC in AKT/Ras and c-Myc mice, while 100% of control mice died of HCC. Therapeutically, microRNA-15a/16-1 promoted a regression of HCC in both mouse models, impaired hepatic enrichment of Tregs, and increased hepatic CTLs. Mechanistically, a significant increase was observed in serum C-C motif chemokine 22 (CCL22) and transcription of Ccl22 in KCs of AKT/Ras and c-Myc mice. MicroRNA-15a/16-1 prevented KCs from overproducing CCL22 by inhibiting nuclear factor-κB that activates transcription of Ccl22. By reducing CCL22 binding to C-C chemokine receptor type 4 on Tregs, microRNA-15a/16-1 impaired Treg chemotaxis. Disrupting the interaction between microRNA-15a/16-1 and nuclear factor-κB impaired the ability of microRNA-15a/16-1 to prevent hepatic Treg accumulation and HCC. Depletion of cluster of differentiation 8⁺ T cells and additional treatment of CCL22 recovered growth of HCC that was fully prevented by microRNA-15a/16.

Conclusions: MicroRNA-15a/16-1 attenuates immunosuppression by disrupting CCL22-mediated communication between KCs and Tregs. MicroRNA-15a/16-1 represents a potential immunotherapy against HCC.

Keywords: Immunosuppression; Immunotherapy; Kupffer Cells; MicroRNA.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Carcinoma, Hepatocellular / genetics
Carcinoma, Hepatocellular / immunology*
Kupffer Cells / immunology*
Kupffer Cells / metabolism
Liver Neoplasms / genetics
Liver Neoplasms / immunology
Liver Neoplasms, Experimental / genetics
Liver Neoplasms, Experimental / immunology*
Mice
MicroRNAs / genetics*
Proto-Oncogene Proteins c-akt
Proto-Oncogene Proteins c-myc
T-Lymphocytes, Regulatory / immunology*
T-Lymphocytes, Regulatory / metabolism
Tumor Escape / genetics
Tumor Escape / immunology*
ras Proteins

Substances

MicroRNAs
Mirn15a microRNA, mouse
Mirn16 microRNA, mouse
Proto-Oncogene Proteins c-myc
Proto-Oncogene Proteins c-akt
ras Proteins