Deciphering and Reversing Immunosuppressive Cells in the Treatment of Hepatocellular Carcinoma

Abstract

Use of immune checkpoint inhibitors (ICIs) in hepatocellular carcinoma (HCC) has been partially successful. However, most HCC patients do not respond to immunotherapy. HCC has been shown to induce several immune suppressor mechanisms in patients. These suppressor mechanisms include involvement of myeloid-derived suppressor cells, regulatory T-cells, functionally impaired dendritic cells (DCs), neutrophils, monocytes, and tumor associated macrophages. The accumulation of immunosuppressive cells may lead to an immunosuppressive tumor microenvironment as well as the dense fibrotic stroma which may contribute to immune tolerance. Our laboratory has been investigating different cellular mechanisms of immune suppression in HCC patients. In vitro as well as in vivo studies have demonstrated that abrogation of the suppressor cells enhances or unmasks tumor-specific antitumor immune responses. Two or three effective systemic therapies including ICIs and/or molecular targeted therapies and the addition of innovative combination therapies targeting immune suppressor cells may lead to increased immune recognition with a greater tumor response. We reviewed the literature for the latest research on immune suppressor cells in HCC, and here we provide a comprehensive summary of the recent studies in this field.

Higher Number of Tumor-Infiltrating PD-L1+ Cells Is Related to Better Response to Multikinase Inhibitors in Hepatocellular Carcinoma

“…Exhausted T cells show upregulated expression of several inhibitory receptors, including PD-1, and its ligand PD-L1 is expressed on various cells, including tumor cells and antigen-presenting cells [ 29 ]. Previous studies have reported immunomodulatory activity of lenvatinib in terms of adaptive immunity [ 10 ].…”

Crosstalk between tumor-associated macrophages and neighboring cells in hepatocellular carcinoma

“…33 Clec4F and Tim4 are expressed in KCs but are not present in infiltrating MoMfs. 33,34 Accounting for approximately 20% of hepatic nonparenchymal cells, KCs have a key role in host defense and coordinate the inflammatory response when they detect pathogens. 35 They are involved in phagocytosis, antigen processing and presentation, and the production of proinflammatory mediators.…”

“…52 Macrophage polarization is influenced by tumor stage and differs among tumors or areas within a tumor. 34 HCC tumor progression was once considered to be associated with a skew in the macrophage phenotype from M1 to M2 phenotypes. 33,53,54 However, recent single-cell analyses have revealed coexisting M1 and M2 signatures in TAMs, indicating that the TAM phenotype may not be simply defined by using the classical M1/M2 model.…”

“…Two markers have been proposed as candidates to distinguish MoMfs from KCs: C-type lectin domain family 4 member F (Clec4F) and T cell immunoglobulin and mucin-domain containing 4 (Tim4) [ 33 ]. Clec4F and Tim4 are expressed in KCs but are not present in infiltrating MoMfs [ 33 , 34 ].…”

“…Macrophages are classified into M1 or M2 according to their phenotypes [ 52 ]. Macrophage polarization is influenced by tumor stage and differs among tumors or areas within a tumor [ 34 ]. HCC tumor progression was once considered to be associated with a skew in the macrophage phenotype from M1 to M2 phenotypes [ 33 , 53 , 54 ].…”