The OX40-OX40L molecule system in leukemia: Expression, function and modulation of NK cell reactivity

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NK cells play an important role in the immunosurveillance of malignancies, especially in leukemia. Their reactivity is guided by a balance of signals from a variety of activating and inhibitory receptors, and several members of the TNF family contribute to the same. In general, many molecules of the TNF family play an important role in the activation, proliferation, and apoptosis of both tumor and immune effector cells. Other investigators reported recently, that upon activation NK cells can express the TNF family member OX40 ligand (OX40L), which primarily is known to be expressed by antigen presenting cells (APC), where it serves as ligand for OX40 on T cells. Alike many other ligands of the TNF family, OX40L is capable to transduce bidirectional signals, and such reverse signaling via OX40L was found to affect the immunomodulatory properties of APC. The functional role of OX40L on NK cells in general and their interaction with tumor cells in particular is yet unknown. In the preliminary work for this project we found that polyklonal NK cells, generated by different protocols for clinical use in adoptive transfer to cancer patients, differentially express OX40L. Signaling via OX40L into NK cells led to activation (upregulation of CD69 and NKp44) and enhanced IFN-gamma production of the NK cells. Furthermore, we already generated and functionally characterized monoclonal antibodies against the cognate receptor OX40. Using these antibodies we could show that OX40 is expressed in a high percentage on patient leukemia cells, predominantly in AML. Stimulation of OX40 lead to release of pathophysiologically relevant cytokines and increased metabolic activity of the leukemia cells. With regard to the functional relevance of the molecule system in the immunosurveillance of malignant cells by NK cells, further preliminary data revealed that OX40-OX40L interaction increased the reactivity of NK cells against target cells.The proposed project now aims to comprehensively analyze the expression of OX40 in a larger cohort of samples from patients with various leukemia entities, and also its suitability as a prognostic marker in the disease. Furthermore we plan to study whether and how OX40 affects proliferation, apoptosis, cytokine production and immunogenicity of leukemia cells. Finally, the influence of OX40L on the reactivity of NK cells will be thoroughly examined with particular emphasis on its role in their interaction with malignant hematopoietic cells. The overall objective of this project thus is to characterize the function of OX40 and its ligand in NK cell immunosurveillance of leukemia cells with the aim of a potential therapeutic modulation in patients.