Hepatocellular carcinoma (HCC) is one of the most common solid tumors with poor clinical prognosis. Novel therapeutic regimens are urgently required for patients with advanced HCC. Both pre-clinical and clinical studies suggest immunotherapy as an attractive alternative for advanced HCC treatment. Natural killer (NK) cells and CD8+ T cells are the most important cytotoxic immune cells involved in cancer treatment and elimination. Reinvigorating the anticancer activity of NK and CD8+ T cells is the fundamental guarantee for the success of immunotherapy in advanced HCC treatment. Therefore, in this review, we aim to summarize the characteristics and roles of NK and CD8+ T cells in HCC development, describe the frontiers of immunotherapy for advanced HCC based on immune checkpoint inhibitors and adoptive cell transfer, and discuss their limitations and scope for future improvement.
Although hepatocellular carcinoma (HCC) is only the fifth-most common cancer worldwide, it ranks second in cancer-related mortality[
The liver contains diverse types of immune cells such as T cells, NK cells, B cells, NKT, and Kupffer cells[
Innate lymphoid cells (ILCs) function as the first line of immune defense against infections and cancers. Paralleling with T cell subsets, ILCs comprise NK cells, ILC1, ILC2, and ILC3, amongst which the NK and ILC1 cells are abundant in the liver[
NK cells have been reported to account for 20%-40% of human hepatic lymphocytes and 10%-20% of murine hepatic lymphocytes, more than half of which
The abundance of tumor-infiltrating CD8+ T cells and the frequency of IFN-γ+ CD8+ T cells were associated with improved survival of HCC patients[
The systemic, local, cellular, and molecular mechanisms of T-cell exhaustion in HCC have been extensively investigated. The hepatic inflammatory microenvironment had been confirmed to be critical for HCC development[
The increased understanding of CD8+ T cells and NK cells promotes the development of effective immunotherapy. These two immune cell populations follow many similar patterns and/or complementary patterns to eliminate cancer cells. Moreover, their activities are regulated by common immune checkpoints. Here, we discuss the application and outcomes of cytotoxic cell-based ICIs and ACT in HCC treatment.
ICIs have displayed impressive efficacy in treating a variety of cancers. An increasing number of studies are being conducted on novel immune checkpoints and their inhibitors. Additionally, studies on ICI-based immunotherapy for advanced HCC treatment are also increasing, with some showing encouraging therapeutic effects.
PD-1 is mainly expressed on CD8+ T cells, whose binding with PD-L1/PD-L2 induces CD8+ T-cell exhaustion[
CTLA-4 is expressed on Treg cells and activated T cells and inhibits T-cell activation by competing for CD80/CD86 with CD28[
The binding of inhibitory killer-immunoglobulin-like receptors (KIRs) expressed on NK cells with HLA class I molecules inhibit the activation of NK cells[
Immune checkpoint blockade leads to recovery of immune response against HCC cells and suppression of tumor growth in HCC. However, most HCC patients still do not achieve clinical benefit from ICI immunotherapy, highlighting the need for creative strategies to improve therapeutic efficacy. First, novel checkpoints need to be identified in HCC. For example, B and T cell lymphocyte attenuator has been found to participate in suppressing CD4+ T cell function in HCC[
NK cells and CD8+ T cells eliminate cancer cells by direct cytotoxicity. In advanced HCC, the scarcity of NK cells and CD8+ T cells in HCC tissues eliminates the ICI-induced anticancer efficacy. In this setting, it is absolutely necessary to adaptively transfer cytotoxic immune cells into patients with advanced HCC.
NK cells have potent anticancer capacity. HLA class I molecule-independent activation endows NK cells with more potential for extensive applications. HLA class I molecules block the NK cell killing though interaction with KIRs or CD94/NKG2A/B on NK cells[
Cytokine-induced killer (CIK) cells generated from blood mononuclear cells cultured with IFN-γ, anti-CD3, and IL-2 show potent anticancer activity[
CAR-T cells have shown tremendous clinical efficacy in the therapy of hematological malignancies[
The success of T cell receptor-genetically engineered T (TCR-T) cells in melanoma treatment has encouraged the use of TCR-T cells in HCC treatment. Autologous T cells forced to express an HBV-specific TCR recognized HBsAg+ HCC cells and decreased HBsAg levels in a patient who underwent liver transplant[
Briefly, DCs are professional antigen-presenting cells with the capacity to prime antigen-specific T-cell immunity. DC vaccines are recognized as promising agents for activating T cells to eliminate cancer cells; their role and functions have been evaluated in some malignancies in clinical trials, including HCC. A phase II study using intravenous vaccination with DCs pulsed with HepG2 lysate was found to be safe and showed evidence of anticancer efficacy in some patients with advanced HCC[
The existence of cancer immunosuppressive microenvironment limits the effector function of adoptive immune cells. Therefore, it is reasonable to improve the cancer immunosuppressive microenvironment to enhance the curative efficacy of adoptive immune cells on HCC. Kodumudi
Following significant therapeutic progress made on the basis of basic research, immunological studies offer a new era of clinical application. Immunotherapy brings a new hope to depressed patients with chronic infection, autoimmune disease, or cancers. More importantly, cytotoxic immune cell-based immunotherapy has markedly improved survival in patients with advanced cancers. The high mortality of patients with advanced HCC owing to resistance to chemotherapy highlights the importance and value of immunotherapy in HCC treatment, although the clinical efficiency has not been as promising as expected. The development of novel ICIs, cytokines, tumor-specific antigens, gene-modified/CAR NK cells, and TCR/CAR CD8+ T cells is expected to improve the curative effect. Furthermore, the flexible combination of immunotherapy and other therapies might offer the much required breakthrough in clinical efficacy of HCC treatment.
Contributed to conception and design of the study and manuscript writing: Li J, Tao L, Wang X
Final approval of manuscripts: Li J, Tao L, Wang X
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This manuscript publication is funded by the Natural Science Foundation of China (#31872741), Anhui Provincial Natural Science Foundation (grant numbers: 1708085QH183 and 1808085QC83), and Young Top Talent Program of Anhui Medical University, and Research Improvement Program of Anhui Medical University.
All authors declared that there are no conflicts of interest.
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© The Author(s) 2020.