Natural killer cells’ functional impairment drives the immune escape of pre-malignant clones in early-stage myelodysplastic syndromes

Early therapeutic interventions following cancer detection are known to extend patient survival. A key challenge is dissecting preneoplastic disease states' biological mechanisms that precede tumorigenesis to slow down disease progression and/or mitigate disease-related comorbidities. Myelodysplastic syndromes (MDS) cannot be cured by currently available pharmacological therapies, which fail to eradicate aberrant hematopoietic stem cells (HSCs), most of which are mutated by the time of diagnosis. Developing early intervention strategies for MDS patients requires a better understanding of aberrant HSC expansion mechanisms. Here, we sought to elucidate how MDS HSCs evade immune surveillance and expand in patients with clonal cytopenias of undetermined significance (CCUS), the pre-malignant stage of MDS. Using multi-omic single-cell approaches and functional in vitro studies, we showed that immune escape at disease initiation is mainly mediated by mutant, dysfunctional natural killer (NK) cells with impaired cytotoxic capability against cancer cells. Preclinical in-vivo studies demonstrated that NK cells infusion from healthy donors efficiently depleted CCUS mutant cells while allowing normal cells to regenerate hematopoiesis. Our findings suggest that early intervention with adoptive cell therapy can prevent or delay the development of MDS.