Programmed Death-Ligand 1 on Antigen-presenting Cells Facilitates the Induction of Antigen-specific Cytotoxic T Lymphocytes: Application to Adoptive T-Cell Immunotherapy

Abstract

Programmed death-ligand 1 (PD-L1) binds to programmed death-1 (PD-1) on activated T cells and contributes to T-cell exhaustion. PD-L1 expressed on antigen-presenting cells (APCs) could be thought to inhibit the induction of Ag-specific cytotoxic T lymphocytes (CTLs) by transducing negative signal into T cells; however, the roles of PD-L1 on APCs have not yet been well examined. Therefore, we evaluated the roles of PD-L1 on APCs in the induction of Ag-specific CTLs. CD3 T cells isolated from cytomegalovirus (CMV)-seropositive healthy donors were stimulated with mature dendritic cells pulsed with CMV pp65-derived HLA-restricted peptides in the presence of anti-PD-L1 blocking antibody. Unexpectedly, PD-L1 blockade resulted in a less efficient induction of CMV-specific CTLs, suggesting that PD-L1 play a positive role in the induction of Ag-specific CTLs. For further evaluations and application to adoptive immunotherapy, we generated K562-based artificial APCs, which were retrovirally transduced with HLA class I molecules and various combinations of CD80/86 and PD-L1. K562/HLA+CD80/86+PD-L1 cells produced significantly higher induction of CMV-specific CTLs than K562/HLA or K562/HLA+CD80/86 cells without causing excessive differentiation or functional exhaustion of the induced CTLs, whereas PD-L1 itself did not have a stimulatory effect. Furthermore, only K562/HLA+CD80/86+PD-L1 cells pulsed with HLA-A*24:02-restricted Wilms tumor 1 (WT1) peptide clearly expanded WT1-specific CTLs from healthy donors. Our findings presumed that PD-L1 expressed on APCs along with CD80/86 enhanced the induction of Ag-specific CTLs probably depending on fine-tuning excessive stimulation of CD80/86, and that K562/HLA+CD80/86+PD-L1 cells has therapeutic potential as a novel type of artificial APCs for adoptive immunotherapy.

Contrasting Roles of the PD-1 Signaling Pathway in Dendritic Cell-Mediated Induction and Regulation of HIV-1-Specific Effector T Cell Functions

“…It is conceivable that when levels of PD-1 are below a certain threshold or blocked with an inhibitor, PD-L1 on the DC preferentially interact with some other costimulatory receptor during the first hours of priming of naive T cells. This hypothesis is supported by studies that indicate a dual role of PD-L1 depending on the context of T cell activation and the possibility of other receptors for PD-L1, as suggested in experimental models (25,28,52,53). Further research is needed to determine if there is a threshold of PD-1 expression at which anti-PD-1 treatment shifts from detrimental to beneficial effects.…”

Dendritic cells loaded with the lysate of tumor cells infected with Newcastle Disease Virus trigger potent anti‑tumor immunity by promoting the secretion of IFN‑γ and IL‑2 from T cells

“…Previous studies have reported that PD-L1 is also expressed at high levels on mature DCs, along with other co-stimulatory molecules (17,27). PD-L1 expression on DCs is necessary for maintaining immune tolerance in humans (28,29).…”

“…PD-L1 expression on DCs is necessary for maintaining immune tolerance in humans (28,29). PD-L1 expression on antigen presenting cells may inhibit the induction of cytotoxic T lymphocytes by transducing negative signals onto T cells; however, it has also been reported that the expression of PD-L1 on antigen presenting cells, along with CD80 and CD86, enhances the induction of antigen-specific cytotoxic T lymphocytes, an effect probably depends on the fine-tuning of the excessive stimulation of CD80 and CD86 (27). In the present study, the NDV-TCL-DCs demonstrated an increasing trend of PD-L1 expression, which was accompanied by a higher level of CD80 and CD86 expression; therefore, NDV-TCL could increase the PD-L1, CD80 and CD86 expression in DCs.…”

EBV up-regulates PD-L1 on the surface of primary monocytes by increasing ROS and activating TLR signaling and STAT3

“…Therefore, targeting PD‐L1–PD1 axis is emerging as a promising strategy to improve the outcome of several anticancer and also antimicrobial therapies . Indeed, PD‐L1 expression can increase on APC surface in the course of chronic infection, promoting the escape of pathogens from immune recognition . Among viruses that persist in the infected host, especially those that induce immune deficiency, such as HIV, up‐regulate PD‐L1 in monocytes or PD1 on T cells, activating the PD‐L1–PD1 axis to further reduce immune response .…”

“…8 Indeed, PD-L1 expression can increase on APC surface in the course of chronic infection, promoting the escape of pathogens from immune recognition. 9,10 Among viruses that persist in the infected host, 11 especially those that induce immune deficiency, such as HIV, up-regulate PD-L1 in monocytes 12 or PD1 on T cells, 13 activating the PD-L1-PD1 axis to further reduce immune response. 14 It has been recently reported that acute infection by Kaposi's Sarcoma Human Herpesvirus (KSHV) also up-regulates PD-L1 surface expression on monocyte surface.…”