A novel spontaneous hepatocellular carcinoma mouse model for studying T-cell exhaustion in the tumor microenvironment

Yu Tzu Liu, Tai Chung Tseng, Ruey Shyang Soong, Chun Yi Peng, Yu Hsing Cheng, Shiu Feng Huang, Tsung Hsien Chuang, Jia Horng Kao, Li Rung Huang*

*Corresponding author for this work

Research output: Contribution to journalJournal Article peer-review

34 Scopus citations

Abstract

Immunotherapy has ushered in a new era of cancer therapy, and this is also applicable to therapy of hepatocellular carcinoma (HCC). In this context, effective development of therapeutic strategies requires an HCC mouse model with known tumor-associated antigens (TAAs) and an HCC growth reporter. We created such a model using hydrodynamic injection and a transposon system to introduce AKT and NRAS and open reading frames (ORFs) encoding surrogate tumor antigens and luciferase into chromosomes of hepatocytes to induce nodular and diffuse tumors in the liver. TAA-specific CD8+ T cells were detected during HCC progression; however, these showed exhausted-like phenotypes and were unable to control tumor growth. Myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAM) from the tumor microenvironment were found to contribute to the suppression of the CD8+ T-cell response. The transposon-based Akt/N-Ras-induced HCC mouse model we developed enables researchers to monitor tumor growth non-invasively and to quantify and characterize endogenous or adoptively transferred TAA-specific CD8+ T-cell responses. These features make it a suitable preclinical model for exploration and evaluation of immune checkpoint inhibitors and cell-based immunotherapies for HCC treatment.

Original languageEnglish
Article number114
JournalJournal for ImmunoTherapy of Cancer
Volume6
Issue number1
DOIs
StatePublished - 07 12 2018

Bibliographical note

Publisher Copyright:
© 2018 The Author(s).

Keywords

  • Hepatocellular carcinoma
  • Immune checkpoint
  • Immunotherapy
  • MDSC
  • T-cell exhaustion
  • Tumor-associated macrophage
  • Tumor-specific T cell

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