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

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.