Association of (tumor-) stem cell characteristics with failure of NKG2D-mediated immunosurveillance

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Available data suggest that only a subset of tumor cells, the so-called tumor stem cells (TSC), are responsible for initiation, maintenance and also relapse after conventional therapy of cancer. However, the development and course of malignant diseases also largely depends on the ability of the transformed cells to evade tumor immunesurveillance, for which NK cells as cytotoxic lymphocytes of innate immunity play an important role. NKG2D is an activating NK receptor, the discovery of which has led to the renaissance of the immune surveillance hypothesis, because its ligands (NKG2DL) are induced upon malignant transformation and potently stimulate anti-tumor immunity. Tumor cells employ various strategies to evade NKG2D-mediated immunesurveillance, which, among others, comprise shedding of NKG2DL from the cell surface to reduce the amount of stimulatory signals for NK cells. Other mechanisms involve direct modulation of NKG2DL-expression, for example via epigenetic regulation. Only little is currently known about the interactions between TSC and the immune system and on whether TSC, as compared to non-TSC, possess special properties to evade immunesurveillance. Our preliminary analyses with leukemia cells of patients with Acute Myeloid Leukemia (AML) reveals that AML-TSC (characterized by expression of CD34, their in vitro clonogenic ability and their in vivo leukaemia-initiating properties upon xenotransplantation in NSG mice) display substantially reduced NKG2DL expression as compared to Non-TSC, which also results in functionally impaired NK cell reactivity specifically against the TSC fraction. Moreover, lack of NKG2DL-expression is able to identify a subpopulation of AML cells displaying enhanced clonogenic capacity independently of CD34 expression, suggesting that lacking NKG2DL expression may be used as a novel marker for the identification of TSC in AML. Based on these data, in the proposed project we aim to comprehensively characterize NKG2DL expression in AML-TSC versus Non-TSC and the consequences for NK-mediated AML immunesurveillance. Moreover, we plan to elucidate the molecular mechanisms responsible for the differential NKG2DL levels in AML-TSC versus Non-TSC as well as the possibilities to therapeutically induce NKG2DL expression in AML-TSC to reinforce anti-tumor immunity. Finally the prevalence of NKG2DL expression on AML-TSC will be correlated with the clinical course of the disease in patients. Taken together, the proposed project serves to further elucidate properties of AML-TSC, especially with regard to their ability to evade tumor immunesurveillance and thereby also holds promise to identify novel immune-sculpting characteristics associated with stemness properties of malignant cells in general.