title: 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.
authors.affiliation: Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Tatsunori
authors.initials: T
authors.lastname: Goto
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Nishida
authors.forename: Erina
authors.initials: E
authors.lastname: Takagi
authors.forename: Kotaro
authors.initials: K
authors.lastname: Miyao
authors.forename: Daisuke
authors.initials: D
authors.lastname: Koyama
authors.forename: Reona
authors.initials: R
authors.lastname: Sakemura
authors.forename: Ryo
authors.initials: R
authors.lastname: Hanajiri
authors.forename: Keisuke
authors.initials: K
authors.lastname: Watanabe
authors.forename: Nobuhiko
authors.initials: N
authors.lastname: Imahashi
authors.forename: Seitaro
authors.initials: S
authors.lastname: Terakura
authors.forename: Makoto
authors.initials: M
authors.lastname: Murata
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Kiyoi
mesh_terms: D019138:Antibodies, Blocking / Q000494:pharmacology; D000914:Antibodies, Viral / Q000097:blood; D000938:Antigen-Presenting Cells / Q000276:immunology* / Q000637:transplantation; D000951:Antigens, Neoplasm / Q000276:immunology; D017209:Apoptosis; D018122:B7-1 Antigen / Q000235:genetics / Q000378:metabolism; D051940:B7-2 Antigen / Q000235:genetics / Q000378:metabolism; D060890:B7-H1 Antigen / Q000276:immunology / Q000378:metabolism*; D003587:Cytomegalovirus / Q000276:immunology*; D003586:Cytomegalovirus Infections / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology* / Q000637:transplantation; D059871:HLA-A24 Antigen / Q000235:genetics / Q000378:metabolism; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000379:methods*; D020014:K562 Cells; D008213:Lymphocyte Activation; D010446:Peptide Fragments / Q000276:immunology; D010750:Phosphoproteins / Q000378:metabolism; D061026:Programmed Cell Death 1 Receptor / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014763:Viral Matrix Proteins / Q000378:metabolism; D009396:Wilms Tumor / Q000276:immunology / Q000378:metabolism*
chemical_list: D019138:Antibodies, Blocking; D000914:Antibodies, Viral; D000951:Antigens, Neoplasm; D018122:B7-1 Antigen; D051940:B7-2 Antigen; D060890:B7-H1 Antigen; C423236:CD274 protein, human; C438506:HLA-A*24:02 antigen; D059871:HLA-A24 Antigen; C105992:PDCD1 protein, human; D010446:Peptide Fragments; D010750:Phosphoproteins; D061026:Programmed Cell Death 1 Receptor; D014763:Viral Matrix Proteins; C065418:cytomegalovirus matrix protein 65kDa