TLR4 induced PD-1 expression on myeloid dendritic cells promotes post-transplant HCC recurrence

Abstract

Background: Immature and paralyzed dendritic cells (DCs) in the tumor microenvironment impede antitumor immunity. PD-1 is known to be not only expressed on T and B lymphocytes but also expressed on myeloid cells such as macrophages and DCs. Recent evidence demonstrates that TLR4 mediates PD-1 expression on DCs, and PD-1+ DCs significantly suppress CD8+ T cell function and antitumor immunity. In this study, we aim to investigate the role of PD-1+ dendritic cells on tumor recurrence after LT. Methods: The expression of PD-1 on DCs was analyzed both in clinical samples and rat orthotopic liver transplantation model. The mechanism of TLR4 on DCs was explored in human monocyte-derived DCs (Mo-DCs) and TLR-4-/- mice. The role of TLR4 signaling on tumor progression was further investigated in mouse orthotopic liver tumor model. Results: Clinically, PD-1 expression was upregulated in CD11c+ myeloid DCs (mDCs) (Fig. 1A), but not in plasmacytoid DCs (pDCs) in liver graft. PD-1 expression on mDCs was also elevated in rats with orthotopic LT (Fig 1B). Recipients with HCC recurrence had higher level of PD-1 expression on CD11c+ cells (Fig 2A). The intragraft mRNA expression of PD-1 was significantly up-regulated and positively correlated with TLR4 after LT (Fig 2B). Functionally, LPS promoted the expression of PD-1, IL-10, TGF-β and MHCII in Mo-DCs. LPS also promoted apoptosis in Mo-DCs (Fig 3A). The PD-1 expression on mDCs was significantly decreased after hepatic I/R injury in TLR4-/- mice (Fig 3B). TLR4 antagonist increased the number of mDCs and suppressed HCC growth in mice after hepatic I/R injury with major hepatectomy (Fig 4). Conclusion: The acute phase graft injury promoted PD-1 expression on DCs via TLR4 signaling, and PD-1+ DCs promoted HCC recurrence after LT.