New insights into checkpoint inhibitor immunotherapy and its combined therapies in hepatocellular carcinoma: from mechanisms to clinical trials

Abstract

Hepatocellular carcinoma (HCC) is one of the most lethal tumors in China and worldwide, although first-line therapies for HCC, such as atezolizumab and bevacizumab, have been effective with good results, the researches on new therapies have attracted much attention. With the deepening research on tumor immunology, the role and operation mechanism of immune cells in the tumor microenvironment (TME) of HCC have been explained, such as programmed cell death protein 1 (PD-1) binding to ligand could cause T cell exhaustion and reduce IFN-γ T cell secretion, cytotoxic T lymphocyte 4 (CTLA-4) and CD28 mediate immunosuppression by competing for B7 protein and disrupting CD28 signal transduction pathway, which also lays the foundation for the development and application of more new immune checkpoint inhibitors (ICIs). The biological behavior of various immune checkpoints has been proved in HCC, such as PD-1, programmed cell death ligand 1 (PD-L1), CTLA-4 and so on, leading to a series of clinical trials. Currently, FDA approved nivolumab, pembrolizumab and nivolumab plus ipilimumab for the treatment of HCC. However, the treatment of ICI has the disadvantages of low response rate and many side effects, so the combination of ICIs and various other therapies (such as VEGF or VEGFR inhibition, neoadjuvant and adjuvant therapy, locoregional therapies) has been derived. Further studies on immune checkpoint mechanisms may reveal new therapeutic targets and new combination therapies in the future.

A Comprehensive Analysis of HAVCR1 as a Prognostic and Diagnostic Marker for Pan-Cancer

“…Tumor immunotherapy is an innovative approach to enhance the immune function of patients and achieve the ultimate goal of killing tumor cells ( Jin et al, 2022 ). We found the HAVCR1 overexpressed in tumor tissue and participated in the immune response, which could be a potential tumor immunotherapy target, such as PD1, PDL1, CTLA4, p53, etc ( Chasov et al, 2021 ; Jin et al, 2022 ). In recent years, CAR-T cell therapy has developed rapidly in tumor treatment, with excellent results in treating blood tumors ( Hou et al, 2021 ).…”

Opportunities and challenges of hepatocellular carcinoma organoids for targeted drugs sensitivity screening

“…Some immunotherapeutic drugs target T cells to activate the tumor-killing ability of T cells, such as PD-1 inhibitors. For example, nivolumab, pembrolizumab, and nivolumab plus ipilimumab are immune checkpoint inhibitors approved by the FDA for the treatment of HCC (51). The lack of the immune microenvironment of the organoid leads to difficulties in the simulation of tumor drug response in immunotherapy, which will undoubtedly limit its application in the testing of such drugs.…”

Nutrition deprivation affects the cytotoxic effect of CD8 T cells in hepatocellular carcinoma

“…In the referenced study, the authors also showed that deprivation of glutamine decreased the secretion of perforin and granzyme B in CD8 + T cells in HCC[ 1 ]. Treatment of immune checkpoint inhibitors by targeting PD-1, programmed death protein-ligand-1 (PD-L1), or cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) has shown clinical effects in HCC patients[ 7 , 8 ]. For example, the U.S. Food and Drug Administration approved the use of nivolumab (anti-PD1) or in combination with ipilimumab or ipilimumab (anti-CTLA-4) for the treatment of patients with HCC in certain conditions[ 9 - 11 ].…”