title: PD-1/PD-L1 interactions contribute to functional T-cell impairment in patients who relapse with cancer after allogeneic stem cell transplantation.
abstract: Tumor relapses remain a serious problem after allogeneic stem cell transplantation (alloSCT), despite the long-term persistence of minor histocompatibility antigen (MiHA)-specific memory CD8(+) T cells specific for the tumor. We hypothesized that these memory T cells may lose their function over time in transplanted patients. Here, we offer functional and mechanistic support for this hypothesis, based on immune inhibition by programmed death-1 (PD-1) expressed on MiHA-specific CD8(+) T cells and the associated role of the PD-1 ligand PD-L1 on myeloid leukemia cells, especially under inflammatory conditions. PD-L1 was highly upregulated on immature human leukemic progenitor cells, whereas costimulatory molecules such as CD80 and CD86 were not expressed. Thus, immature leukemic progenitor cells seemed to evade the immune system by inhibiting T-cell function via the PD-1/PD-L1 pathway. Blocking PD-1 signaling using human antibodies led to elevated proliferation and IFN-γ production of MiHA-specific T cells cocultured with PD-L1-expressing leukemia cells. Moreover, patients with relapsed leukemia after initial MiHA-specific T-cell responses displayed high PD-L1 expression on CD34(+) leukemia cells and increased PD-1 levels on MiHA-specific CD8(+) T cells. Importantly, blocking PD-1/PD-L1 interactions augment proliferation of MiHA-specific CD8(+) memory T cells from relapsed patients. Taken together, our findings indicate that the PD-1/PD-L pathway can be hijacked as an immune escape mechanism in hematological malignancies. Furthermore, they suggest that blocking the PD-1 immune checkpoint offers an appealing immunotherapeutic strategy following alloSCT in patients with recurrent or relapsed disease.
authors.affiliation: Departments of Laboratory Medicine, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
authors.forename: Wieger J
authors.initials: WJ
authors.lastname: Norde
authors.forename: Frans
authors.initials: F
authors.lastname: Maas
authors.forename: Willemijn
authors.initials: W
authors.lastname: Hobo
authors.forename: Alan
authors.initials: A
authors.lastname: Korman
authors.forename: Michael
authors.initials: M
authors.lastname: Quigley
authors.forename: Michel G D
authors.initials: MG
authors.lastname: Kester
authors.forename: Konnie
authors.initials: K
authors.lastname: Hebeda
authors.forename: J H Frederik
authors.initials: JH
authors.lastname: Falkenburg
authors.forename: Nicolaas
authors.initials: N
authors.lastname: Schaap
authors.forename: Theo M
authors.initials: TM
authors.lastname: de Witte
authors.forename: Robbert
authors.initials: R
authors.lastname: van der Voort
authors.forename: Harry
authors.initials: H
authors.lastname: Dolstra
mesh_terms: D015703:Antigens, CD / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D018122:B7-1 Antigen / Q000096:biosynthesis; D051940:B7-2 Antigen / Q000096:biosynthesis; D060890:B7-H1 Antigen; D018920:Coculture Techniques; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007156:Immunologic Memory; D007249:Inflammation; D007371:Interferon-gamma / Q000494:pharmacology; D007951:Leukemia, Myeloid / Q000276:immunology* / Q000473:pathology / Q000601:surgery; D015778:Minor Histocompatibility Antigens / Q000276:immunology; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D014411:Neoplastic Stem Cells / Q000276:immunology / Q000378:metabolism; D061026:Programmed Cell Death 1 Receptor; D058485:Receptors, Purinergic P2X5 / Q000276:immunology; D012008:Recurrence; D037182:T-Cell Antigen Receptor Specificity; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D014184:Transplantation, Homologous; D019139:Tumor Escape / Q000276:immunology / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D015703:Antigens, CD; D051017:Apoptosis Regulatory Proteins; D018122:B7-1 Antigen; D051940:B7-2 Antigen; D060890:B7-H1 Antigen; C423236:CD274 protein, human; C497964:CD86 protein, human; D015778:Minor Histocompatibility Antigens; D009363:Neoplasm Proteins; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D058485:Receptors, Purinergic P2X5; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma