A novel spontaneous hepatocellular carcinoma mouse model for studying T-cell exhaustion in the tumor microenvironment
Journal
Journal for ImmunoTherapy of Cancer
Journal Volume
6
Journal Issue
1
Pages
114
Date Issued
2018
Author(s)
Liu Y.-T.
Soong R.-S.
Peng C.-Y.
Cheng Y.-H.
Huang S.-F.
Chuang T.-H.
Huang L.-R.
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. ? 2018 The Author(s).
Subjects
Hepatocellular carcinoma; Immune checkpoint; Immunotherapy; MDSC; T-cell exhaustion; Tumor-associated macrophage; Tumor-specific T cell
SDGs
Other Subjects
CD19 antigen; programmed death 1 ligand 1; programmed death 1 ligand 2; programmed death 1 receptor; protein kinase B; tumor marker; AKT1 gene; animal experiment; animal model; animal tissue; apoptosis; Article; carcinogenesis; CD4+ T lymphocyte; CD8+ T lymphocyte; cell proliferation; controlled study; flow cytometry; gene; genetic transfection; immune response; immunohistochemistry; immunosuppressive treatment; liver cell carcinoma; luciferase assay; male; mouse; nonhuman; priority journal; tumor growth; tumor microenvironment; upregulation; adoptive transfer; animal; disease model; gene expression; human; immunocompromised patient; immunology; liver cell carcinoma; liver tumor; macrophage; metabolism; myeloid-derived suppressor cell; oncogene; oncogene ras; pathology; reporter gene; T lymphocyte; tumor associated leukocyte; tumor microenvironment; Adoptive Transfer; Animals; Biomarkers, Tumor; Carcinoma, Hepatocellular; Disease Models, Animal; Gene Expression; Genes, ras; Genes, Reporter; Humans; Immunocompromised Host; Immunohistochemistry; Liver Neoplasms; Lymphocytes, Tumor-Infiltrating; Macrophages; Male; Mice; Myeloid-Derived Suppressor Cells; Oncogenes; Proto-Oncogene Proteins c-akt; T-Lymphocytes; Tumor Microenvironment
Publisher
BioMed Central Ltd.
Type
journal article