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Targeting polo-like kinase 1 suppresses essential functions of alloreactive T cells

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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 p21WAF/CIP1, p27Kip1, 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.

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Abbreviations

aGvHD:

Acute graft-versus-host disease

allo DC:

Allogeneic dendritic cells

ASCT:

Allogeneic stem cell transplantation

Tallo :

Alloreactive T cells

C-3:

Caspase-3

CFSE:

5-(and 6-)Carboxyfluorescein diacetate succinimidyl ester

CI:

Combination indices

CBA:

Cytometric bead array

DC:

Dendritic cells

DMAG:

17-(Dimethylaminoethylamino)-17-demethoxygeldanamycin

DMSO:

Dimethyl sulfoxide

FL:

Full length

GM-CSF:

Granulocyte macrophage colony-stimulating factor

GSK:

GSK461364 analogue 1

Hsp90:

Heat shock protein 90

IL:

Interleukin

MLR:

Mixed leukocyte reaction

PLK1:

Polo-like kinase 1

PI:

Propidiumiodide

rh:

Recombinant human

TNF:

Tumor necrosis factor

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Acknowledgments

This work was supported by Grants from the Deutsche Forschungsgemeinschaft (KFO 216).

Author contributions

C.B. performed the research, analyzed the data; C.B., M.S.T., H.E. and M.C. designed the research; C.B., M.S.T., H.E. and M.C. wrote the manuscript.

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Authors and Affiliations

  1. Division of Hematology and Oncology, Department of Internal Medicine II, University Hospital of Würzburg, Würzburg, Germany

    Carsten Berges, Manik Chatterjee, Max S. Topp & Hermann Einsele

  2. Comprehensive Cancer Center Mainfranken, University Hospital of Würzburg, Würzburg, Germany

    Manik Chatterjee

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  1. Carsten Berges
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Correspondence to Carsten Berges.

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Berges, C., Chatterjee, M., Topp, M.S. et al. Targeting polo-like kinase 1 suppresses essential functions of alloreactive T cells. Immunol Res 64, 687–698 (2016). https://doi.org/10.1007/s12026-015-8778-2

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