title: T cells remaining after intensive chemotherapy for acute myelogenous leukemia show a broad cytokine release profile including high levels of interferon-gamma that can be further increased by a novel protein kinase C agonist PEP005.
abstract: Cytokines are released during T cell activation, including the potentially anti-leukemic interferon-gamma (IFNgamma), 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 IFNgamma 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 IFNgamma and GM-CSF levels showed a significant correlation and were generally higher than the other cytokine levels. Higher IFNgamma 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 TNFalpha 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 IFNgamma 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 IFNgamma and GM-CSF receptors which differs between AML patients.
authors.affiliation: Section for Hematology, Institute of Medicine, The University of Bergen and Haukeland University Hospital, 5021 Bergen, Norway. elisabeth.ersvar@med.uib.no
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Ersvaer
authors.forename: Peter
authors.initials: P
authors.lastname: Hampson
authors.forename: Kimberley
authors.initials: K
authors.lastname: Hatfield
authors.forename: Elling
authors.initials: E
authors.lastname: Ulvestad
authors.forename: Øystein
authors.initials: Ø
authors.lastname: Wendelbo
authors.forename: Janet M
authors.initials: JM
authors.lastname: Lord
authors.forename: Bjørn Tore
authors.initials: BT
authors.lastname: Gjertsen
authors.forename: Øystein
authors.initials: Ø
authors.lastname: Bruserud
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use; D002478:Cells, Cultured; D016207:Cytokines / Q000187:drug effects* / Q000378:metabolism; D004224:Diterpenes / Q000494:pharmacology*; D004952:Esters / Q000494:pharmacology*; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000276:immunology*; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology*; D008231:Lymphopenia / Q000139:chemically induced; D008297:Male; D008875:Middle Aged; D011493:Protein Kinase C / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism
chemical_list: C486592:3-ingenyl angelate; D000970:Antineoplastic Agents; D016207:Cytokines; D004224:Diterpenes; D004952:Esters; D007371:Interferon-gamma; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D011493:Protein Kinase C