title: Targeting polo-like kinase 1 suppresses essential functions of alloreactive T cells.
abstract: Acute graft-versus-host disease (aGvHD) is still a major cause of transplant-related mortality after allogeneic stem cell transplantation (ASCT). It requires immunosuppressive treatments that broadly abrogate T cell responses including beneficial ones directed against tumor cells or infective pathogens. Polo-like kinase 1 (PLK1) is overexpressed in many cancer types including leukemia, and clinical studies demonstrated that targeting PLK1 using selective PLK1 inhibitors resulted in inhibition of proliferation and induction of apoptosis predominantly in tumor cells, supporting the feasibility of PLK1 as target for anticancer therapy. Here, we show that activation of alloreactive T cells (Tallo) up-regulate expression of PLK1, suggesting that PLK1 is a potential new candidate for dual therapy of aGvHD and leukemia after ASCT. Inhibition of PLK1, using PLK1-specific inhibitor GSK461364A selectively depletes Tallo by preventing activation and by inducing apoptosis in already activated Tallo, while memory T cells are preserved. Activated Tallo cells which survive exposure to PLK1 undergo inhibition of proliferation by induction of G2/M cell cycle arrest, which is accompanied by accumulation of cell cycle regulator proteins p21(WAF/CIP1), p27(Kip1), p53 and cyclin B1, whereas abundance of CDK4 decreased. We also show that suppressive effects of PLK1 inhibition on Tallo were synergistically enhanced by concomitant inhibition of molecular chaperone Hsp90. Taken together, our data suggest that PLK1 inhibition represents a reasonable dual strategy to suppress residual tumor growth and efficiently deplete Tallo, and thus provide a rationale to selectively prevent and treat aGvHD.
authors.affiliation: Division of Hematology and Oncology, Department of Internal Medicine II, University Hospital of Würzburg, Würzburg, Germany. carsten.berges@gmx.de.
authors.forename: Carsten
authors.initials: C
authors.lastname: Berges
authors.affiliation: Division of Hematology and Oncology, Department of Internal Medicine II, University Hospital of Würzburg, Würzburg, Germany.|Comprehensive Cancer Center Mainfranken, University Hospital of Würzburg, Würzburg, Germany.
authors.forename: Manik
authors.initials: M
authors.lastname: Chatterjee
authors.affiliation: Division of Hematology and Oncology, Department of Internal Medicine II, University Hospital of Würzburg, Würzburg, Germany.
authors.forename: Max S
authors.initials: MS
authors.lastname: Topp
authors.affiliation: Division of Hematology and Oncology, Department of Internal Medicine II, University Hospital of Würzburg, Würzburg, Germany.
authors.forename: Hermann
authors.initials: H
authors.lastname: Einsele
mesh_terms: D000208:Acute Disease; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D048708:Cell Growth Processes; D045744:Cell Line, Tumor; D006086:Graft vs Host Disease / Q000209:etiology / Q000276:immunology* / Q000517:prevention & control; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors; D006801:Humans; D007156:Immunologic Memory; D007519:Isoantigens / Q000276:immunology; D007938:Leukemia / Q000209:etiology / Q000276:immunology* / Q000517:prevention & control; D008213:Lymphocyte Activation; D008212:Lymphocyte Depletion; D058990:Molecular Targeted Therapy; D011183:Postoperative Complications / Q000276:immunology* / Q000517:prevention & control; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D033581:Stem Cell Transplantation; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*; D013876:Thiophenes / Q000494:pharmacology*; D014184:Transplantation, Homologous; D000097869:Polo-Like Kinase 1
chemical_list: D018797:Cell Cycle Proteins; D018841:HSP90 Heat-Shock Proteins; D007519:Isoantigens; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D013876:Thiophenes; D000097869:Polo-Like Kinase 1; C544835:GSK 461364A
keywords: Acute graft-versus-host disease; Allogeneic stem cell transplantation; Alloreactive T cell depletion; Transplant conditioning