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T cells remaining after intensive chemotherapy for acute myelogenous leukemia show a broad cytokine release profile including high levels of interferon-γ that can be further increased by a novel protein kinase C agonist PEP005

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Abstract

Cytokines are released during T cell activation, including the potentially anti-leukemic interferon-γ (IFNγ), but also the hematopoietic growth factor granulocyte-macrophage colony-stimulating factor (GM-CSF) that enhance proliferation and inhibit apoptosis of acute myelogenous leukemia (AML) cells. In the present study we investigated the release of IFNγ and GM-CSF by circulating T cells in AML patients with chemotherapy-induced cytopenia. T cells were activated with anti-CD3 plus anti-CD28 in a whole-blood assay in the presence of their natural cytokine network. We examined 63 samples derived from 16 AML patients during 28 chemotherapy cycles. Activated T cells showed a broad cytokine release profile, but IFNγ and GM-CSF levels showed a significant correlation and were generally higher than the other cytokine levels. Higher IFNγ and GM-CSF responses were associated with a low CD4:CD8 ratio, older patient age and no ongoing chemotherapy indicating potential utility of T cell activation regimes for the older AML patient. The cytokine levels could be further increased by the novel protein kinase C agonist PEP005, which also induced significant production of IL2 and TNFα which could contribute to anti-tumor effects in AML patients. We conclude that remaining T cells after intensive AML therapy show a broad cytokine release profile including high and significantly correlated levels of potentially anti-leukemic IFNγ and the AML growth factor GM-CSF. The final outcome of an AML-initiated T cell cytokine response will thus depend on the functional characteristics of the AML cells, in particular the relative expression of IFNγ and GM-CSF receptors which differs between AML patients.

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Acknowledgments

The work was supported by the Norwegian Cancer Society and the European commission (LSHB-CT-2004–503467). The technical assistance of Kristin Paulsen and Aina Kvinnsland is gratefully acknowledged.

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Authors and Affiliations

  1. Section for Hematology, Institute of Medicine, The University of Bergen and Haukeland University Hospital, 5021, Bergen, Norway

    Elisabeth Ersvær, Kimberley Hatfield, Øystein Wendelbo, Bjørn Tore Gjertsen & Øystein Bruserud

  2. Division for Infectious Diseases, The University of Bergen and Haukeland University Hospital, Bergen, Norway

    Øystein Wendelbo

  3. MRC Centre for Immune Regulation, The University of Birmingham, Birmingham, UK

    Peter Hampson & Janet M. Lord

  4. Department of Microbiology and Immunology and The Gade Institute, Haukeland University Hospital and The University of Bergen, Bergen, Norway

    Elling Ulvestad

Authors
  1. Elisabeth Ersvær
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  2. Peter Hampson
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  3. Kimberley Hatfield
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  4. Elling Ulvestad
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  5. Øystein Wendelbo
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  6. Janet M. Lord
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  7. Bjørn Tore Gjertsen
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  8. Øystein Bruserud
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Correspondence to Elisabeth Ersvær.

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Ersvær, E., Hampson, P., Hatfield, K. et al. T cells remaining after intensive chemotherapy for acute myelogenous leukemia show a broad cytokine release profile including high levels of interferon-γ that can be further increased by a novel protein kinase C agonist PEP005. Cancer Immunol Immunother 56, 913–925 (2007). https://doi.org/10.1007/s00262-006-0236-5

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  • DOI: https://doi.org/10.1007/s00262-006-0236-5

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