Current Perspectives on the Immunosuppressive Niche and Role of Fibrosis in Hepatocellular Carcinoma and the Development of Antitumor Immunity

Immune checkpoint inhibitors have become the mainstay of treatment for hepatocellular carcinoma (HCC). However, they are ineffective in some cases. Previous studies have reported that genetic alterations in oncogenic pathways such as Wnt/β-catenin are the important triggers in HCC for primary refrac...

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Bibliographic Details
Published in:Journal of Histochemistry & Cytochemistry 2022-01, Vol.70 (1), p.53-81
Main Authors: Aoki, Tomoko, Nishida, Naoshi, Kudo, Masatoshi
Format: Article
Language:English
Subjects:
Animals
Carcinoma, Hepatocellular - immunology
Carcinoma, Hepatocellular - pathology
Carcinoma, Hepatocellular - therapy
Fibrosis - immunology
Fibrosis - pathology
Fibrosis - therapy
Humans
Immune Checkpoint Inhibitors - pharmacology
Immunotherapy
Liver Neoplasms - immunology
Liver Neoplasms - pathology
Liver Neoplasms - therapy
Reviews
Stem Cell Niche - drug effects
Stem Cell Niche - immunology
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Summary:Immune checkpoint inhibitors have become the mainstay of treatment for hepatocellular carcinoma (HCC). However, they are ineffective in some cases. Previous studies have reported that genetic alterations in oncogenic pathways such as Wnt/β-catenin are the important triggers in HCC for primary refractoriness. T-cell exhaustion has been reported in various tumors and is likely to play a prominent role in the emergence of HCC due to chronic inflammation and cirrhosis-associated immune dysfunction. Immunosuppressive cells including regulatory T-cells and tumor-associated macrophages infiltrating the tumor are associated with hyperprogressive disease in the early stages of immune checkpoint inhibitor treatment. In addition, stellate cells and tumor-associated fibroblasts create an abundant desmoplastic environment by producing extracellular matrix. This strongly contributes to epithelial to mesenchymal transition via signaling activities including transforming growth factor beta, Wnt/β-catenin, and Hippo pathway. The abundant desmoplastic environment has been demonstrated in pancreatic ductal adenocarcinoma and cholangiocarcinoma to suppress cytotoxic T-cell infiltration, PD-L1 expression, and neoantigen expression, resulting in a highly immunosuppressive niche. It is possible that a similar immunosuppressive environment is created in HCC with advanced fibrosis in the background liver. Although sufficient understanding is required for the establishment of immune therapies of HCC, further investigations are still required in this field:
ISSN:0022-1554
1551-5044
DOI:10.1369/00221554211056853