Immunobiology and immunotherapy of HCC: spotlight on innate and innate-like immune cells

Abstract

Immune-based therapies such as immune checkpoint inhibitors have revolutionized the systemic treatment of various cancer types. The therapeutic application of monoclonal antibodies targeting inhibitory pathways such as programmed cell death-1(PD-1)/ programmed cell death ligand 1 (PD-L1) and CTLA-4 to cells of the adaptive immune system has recently been shown to generate meaningful improvement in the clinical outcome of hepatocellular carcinoma (HCC). Nevertheless, current immunotherapeutic approaches induce durable responses in only a subset of HCC patients. Since immunologic mechanisms such as chronic inflammation due to chronic viral hepatitis or alcoholic and nonalcoholic fatty liver disease play a crucial role in the initiation, development, and progression of HCC, it is important to understand the underlying mechanisms shaping the unique tumor microenvironment of liver cancer. The liver is an immunologic organ with large populations of innate and innate-like immune cells and is exposed to bacterial, viral, and fungal antigens through the gut-liver axis. Here, we summarize and highlight the role of these cells in liver cancer and propose strategies to therapeutically target them. We also discuss current immunotherapeutic strategies in HCC and outline recent advances in our understanding of how the therapeutic potential of these agents might be enhanced.

Immunmodulatory Treatment Strategies of Hepatocellular Carcinoma: From Checkpoint Inhibitors Now to an Integrated Approach in the Future

“…The primary endpoints, OS and PFS, were improved by the use of pembrolizumab but did not meet their pre-specified statistical significance [30]. The use As discussed recently [23,24], HCC represents a tumor which could be especially attractive for using immunomodulatory drugs because: (i) the liver itself covers important immune functions by filtering infectious agents from the blood flow or from the gastrointestinal system and, therefore, is permanently exposed to various antigens requiring a certain immune tolerability, and, (ii) HCC arises from typical inflammatory conditions (cirrhosis, hepatitis, see above) and can thus be considered an inflammation-related cancer with potential immunogenicity. The currently poor prognosis of HCC patients at advanced stages requires continuous efforts in identifying specific and more effective anti-HCC approaches.…”

The cGAS-STING Pathway: Novel Perspectives in Liver Diseases

“…Recently, cancer immunotherapy has emerged as an effective therapy for various types of cancers ( 83 ). Accumulating evidence demonstrates the vital role of the innate immune system in liver cancer immunosurveillance and immunotherapy ( 84 ). During tumorigenesis, tumor cell death and genome instability could lead to abnormal localization of genomic DNA in the cytosol and micronuclei formation ( 16 , 85 ).…”

Prognostic Implication of a Novel Metabolism-Related Gene Signature in Hepatocellular Carcinoma

“…Immune-based therapies have become a systematic treatment method for improving the prognosis of advanced cancers (17). Therefore, we further analyzed the correlation between the risk groups and the expression levels of immune checkpoint proteins.…”