Cellular based immunotherapy for primary liver cancer

Abstract

Primary liver cancer (PLC) is a common malignancy with high morbidity and mortality. Poor prognosis and easy recurrence on PLC patients calls for optimizations of the current conventional treatments and the exploration of novel therapeutic strategies. For most malignancies, including PLC, immune cells play crucial roles in regulating tumor microenvironments and specifically recognizing tumor cells. Therefore, cellular based immunotherapy has its instinctive advantages in PLC therapy as a novel therapeutic strategy. From the active and passive immune perspectives, we introduced the cellular based immunotherapies for PLC in this review, covering both the lymphoid and myeloid cells. Then we briefly review the combined cellular immunotherapeutic approaches and the existing obstacles for PLC treatment.

Keywords: Cellular based immunotherapy; Combined immunotherapy; Lymphoid cell; Myeloid cell; Primary liver cancer.

Fig. 1

Cellular based immunotherapy in liver cancer. Based on myeloid or lymphoid immune cells, strategies are attempted for liver cancer therapy. In myeloid cell group, DC vaccine, engineered Mφ and depletion of immune suppressors are undergoing research for hepatoma treatment. For lymphoid cells, strategies such as T/NK cell engineering, Tregs/Bregs depletion and molecular regulatory intervenes are also under study. DC, dendritic cell; Mφ, macrophage; Tregs, regulatory T cells; Bregs, regulatory B cells; FOXP3, forkhead box protein P3; GITRL, ligand to Tregs evoked glucocorticoid induced tumor necrosis factor receptor; TCR-T, T cell receptor engineered T cells; CAR-T, chimeric antibody receptor engineered T Cells; HBV, hepatitis B virus; HCV, hepatitis C virus; HLA-A2, human leukocyte antigen-A2; AFP, A-fetoprotein; GPC3, Glypican-3; NKG2D, NK group 2 member D; VEGF, vascular endothelial growth factor; EGFRvIII, epidermal growth factor receptor variant III; TIM-1⁺, T cell immunoglobulin mucin domain-1 positive; PD-1, programmed cell death-1; CXCL9, chemokine C-X-C motif chemokine ligand-9; IL, interleukin; CD169, cluster of differentiation 169; CD44, cluster of differentiation 44; CD133, cluster of differentiation 133; CD40, cluster of differentiation 40; CD160, cluster of differentiation 160; CD96, cluster of differentiation 96; CD11b, cluster of differentiation 11b; CD27, cluster of differentiation 27; CD3, cluster of differentiation 3; DAP10, DNAX-activating protein 10

Fig. 2

Tregs interact with immune cells and the therapies in liver cancer. Tregs suppress anti-liver cancer immunity via interacting with several immune cells. Firstly, Tregs inhibit APCs’ function in liver cancer, currently known mechanisms like CTLA-4 ligand expression to down-regulate DCs’ CD80/86 and IL-10 secretion to inhibit DCs maturation, TLR-4 signal mediated immune suppression with macrophage participant. And the APCs suppression may be rescued by drugs like cabozantinib and CTLA4 blockade. Secondly, Tregs suppress FOXP3⁻ T cells in liver cancer such as effector T cell (consuming IL-2 with highly expressed CD25; PD-1 correlated dysregulation) and γδ T cell (depending on TGF β and IL-10), which can be partially blocked by GITRL therapy. And regulatory T cell itself can be depressed by CD4⁺CD25⁺ Tregs’ proportion decreaser solanine and FOXP3 expression inhibitor astragalus polysaccharides for liver cancer therapy. CTLA-4, cytotoxic T lymphocyte associated antigen-4; IL-2, interleukin-2; IL-10, interleukin-10; TLR-4, Toll like receptor-4; PD-1, programmed cell death-1; PD-L1, programmed cell death-ligand 1; TGF β, transforming growth factor β; GITRL, glucocorticoid induced tumor necrosis factor receptor ligand; CD25, cluster of differentiation 25