New pharmaco-therapeutic approaches to improve natural killer cell activity against selected lymphoma cell lines
Project management at the University of Würzburg:
Cancer immuno-surveillance depends on the mutual interaction between tumor cells and different immune cell subsets. Unfortunately, the presence of tumor derived inhibitory factors as well as a lack of danger signals often preclude a proper activation of innate immune cells like natural killer (NK) cells. This is especially important as prior activation of the innate immune system would also greatly improve tumor recognition by antigen-specific T-cells. Consequently, the limited success of cellular immunotherapies might be improved by pharmacologic approaches, which enhance NK cell cytotoxicity and target cell susceptibility. Multi-targeted tyrosine kinase inhibitors (TKIs) may be useful tools in this regard since the tyrosine kinases (TKs) targeted are not only crucial for tumor growth, but also involved in the signal transduction pathways of different immune cell subsets. This hypothesis is supported by clinical data that indicate an enhanced anti-leukemic response in some patients under TKI treatment associated with NK or CD8+ T large granular lymphocyte expansion. In this research project we will thus analyse systematically the influence of clinically relevant TKIs on the first line of defense against malignancies. We will evaluate the effects of a horizontal TKI focusing on receptor kinases and one with primary focus on intracellular kinases, and a vertical TKI equally targeting the intracellular and surface receptor tyrosine kinases. This should lead to the development of a mechanistic hierarchy of these TKIs with regard to their ability to enhance NK cell functions (cytotoxicity, cytokine secretion) against selected lymphoma cell lines. In a second step, the results will be tested directly ex vivo by evaluating blood NK cell effector functions of cancer patients under TKI treatment vs. healthy controls. Understanding the modulation of signal transduction by TKIs in NK cells essential for immune surveillance provides the rational for the development of their potential adjuvant use in NK cell based immune therapeutic approaches.
Projekt period: from 01.2010 to 12.2012
Sonstige öffentliche Mittel ( Deutsche Krebshilfe ) ,Granting date: 26.10.2009