Adaptation of NK cell function in ATM deficiency

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Ataxia telangiectasia (A-T) is a genetic instability syndrome that causes a progressive multisystemic disorder as a consequence of mutations in the gene encoding for the serine-threonine kinase Ataxia Telangiectasia-mutated (ATM). Besides neurodegenerative symptoms, patients are suffering from severe and often life-threatening lung disease and hematopoietic malignancies. Current treatments only slightly alleviate diseases symptoms, and no curative treatment is available. Our grant proposal tackles two major questions relating to the functionality and to the possible therapeutic benefit of Natural Killer (NK) cells in ATM deficiency. One major aim is focused on the analyses of the maturation, responsiveness and functional adaption of NK cells in mice and humans with genetic defects in ATM. We attempt to unravel the impact of ATM deficiency on NK cell fitness and NK cell-mediated cancer immunosurveillance. Secondly, we want to explore the therapeutic benefit of an adoptive transfer of NK cells in the context of allo-stem cell transplantation (allo-SCT) in Atm-deficient mice. Ex vivo cytokine-activated and adoptively transferred NK cells may not only strengthen NK cell immunity in ATM-deficiency, but will likely also improve engraftment and immune reconstitution following allo-SCT. This strategy could be especially interesting in A-T patients that are highly sensitive for radiotherapy and therefore require alternate approaches of conditioning.