Increased both PD–L1 and PD–L2 expressions on monocytes of patients with hepatocellular carcinoma was associated with a poor prognosis

Abstract

Anti-programmed cell death-1 (PD-1) antibodies has been approved to treat HCC. Some PD-1 ligands (PD–L1 and PD–L2) negative tumors respond to treatment of anti-PD-1 antibodies, and this fact may be caused by the expression of PD-1 ligands on non-tumor cells. PD–L1 was recently found to be expressed on CD14+ cells from cancer patients. We investigate PD-1 ligands expression on CD14+ cells of patients with HCC and the role of CD14+ cells in an antitumor response. In this study, 87 patients diagnosed with HCC were enrolled. CD14+ cells from patients with HCC expressed PD–L1 (4.5–95.5%) and PD–L2 (0.2–95.0%). According to cut-off values, we classified patients as those either with PD–L1+PD–L2+CD14+ cells or other types of CD14+ cells. The overall survival of patients with PD–L1+PD–L2+CD14+ cells was shorter than that of patients with other types of CD14+ cells (p = 0.0023). PD–L1+PD–L2+CD14+ cells produced IL-10 and CCL1, and showed little tumoricidal activity against HepG2 cells. The tumoricidal activity of CD8+ cells from patients with PD–L1+PD–L2+CD14+ cells were suppressed by co-cultivation with CD14+ cells from the syngeneic patient. Furthermore, anti-PD-1 antibody restored their tumoricidal activity of CD8+ cells. In conclusion, some patients with HCC have PD–L1+PD–L2+CD14+ cells that suppress their antitumor response. These inhibitory functions of CD14+ cells may be associated with a poor prognosis in these patients.

Programmed Death 1 Ligand Expression in the Monocytes of Patients with Hepatocellular Carcinoma Depends on Tumor Progression

“…Specifically, PD-L1 + PD-L2 + CD14 + cells were cocultured with CD8 + cells isolated from syngeneic patients, resulting in the antitumor activity of CD8 + cells being suppressed against HepG2 cells and Huh7 cells. Meanwhile, their antitumor activity was restored following treatment with a PD-1 antibody, that is, CD14 + cells suppressed the antitumor activity of CD8 + cells via the PD-L/PD-1 pathway, which can be restored by PD-1 antibodies [ 19 ]. Similarly, it has been reported that PD-L1 on dendritic cells mediates CD8 + T-cell antitumor activity [ 31 ].…”

“…Third, PD-L1/L2 expression in other antitumor effector cells, such as CD4 T cells, CD8 T cells, B cells, and mast cells, were not examined. However, we have previously reported that the expression of both PD-L1 and PD-L2 in monocytes is associated with poor prognosis [ 19 ]. We conclude that monocytes expressing both PD-L1 and PD-L2 may play a key role in antitumor immunity.…”

“…Meanwhile, in our recent report, we showed that the monocytes of patients with advanced-stage HCC expressed PD-L1 and PD-L2 and suppressed the antitumor immune response of other effector cells. Notably, these patients had a poor prognosis [ 19 ]. However, the impact of these cells on the host immune response against HCC is unknown.…”

Anti-PD-1/PD-L1 Based Combination Immunotherapy to Boost Antigen-Specific CD8+ T Cell Response in Hepatocellular Carcinoma

“…Additionally, M1 macrophages can induce PD-L1 expression on hepatocarcinoma cells by IL-1β effect [ 64 ]. These data suggest an important role of macrophages in modulating CD8 T cell exhaustion in HCC by promoting a immunotolerant environment [ 65 ] and by up-regulating themselves both PD-L1 and PD-L2 expression [ 66 ]. However, PD-L1 expression on macrophages could also have a positive input because it correlates with CD8 T cell infiltration and increased OS after treatment [ 67 ], probably in the case of M1-like macrophage infiltration [ 17 ].…”

Immuno-Oncotherapeutic Approaches in Advanced Hepatocellular Carcinoma

“…Studies have shown HCC cells with overexpression of programmed death-1 (PD-1) can elicit weaker immune reactions by suppressing T-cell response and resulting in uncontrolled cell division [ 8 , 9 ]. Amplified MHC class II molecule expression in hepatocellular carcinoma result in T-cell anergy as co-stimulatory molecules cannot be identified by other antigen-presenting cells.…”