CD56 as a marker of an ILC1-like population with NK cell properties that is functionally impaired in AML

An understanding of natural killer (NK) cell physiology in acute myeloid leukemia (AML) has led to the use of NK cell transfer in patients, demonstrating promising clinical results. However, AML is still characterized by a high relapse rate and poor overall survival. In addition toconventional NKs that can be considered the innate counterparts of CD8 T cells, another family of innate lymphocytes has been recently described with phenotypes and functions mirroring those of helper CD4 T cells. Here, in blood and tissues, we identified a CD56+ innate cellpopulation harboring mixed transcriptional and phenotypic attributes of conventional helper innate lymphoid cells (ILCs) and lytic natural killer (NK) cells. These CD56+ ILC1-like cells possess strong cytotoxic capacities that were impaired in AML patients at diagnosis but were restored upon remission. Their cytotoxicity is KIR-independent and relies on the expression of TRAIL, NKp30, NKp80 and NKG2A. However, the presence of leukemic blasts, HLA-E positive cells and/or TGFb1 strongly affected their cytotoxic potential, at least partially by reducing theexpression of cytotoxic related molecules. Notably, CD56+ ILC1-like cells were also present in the NK cell preparations used in NK-transferbased clinical trials. Overall, we identified a NK cell-related CD56+ ILC population involved in tumor immunosurveillance in humans, and we propose that restoring their functions with anti-NKG2A antibodies and/or small molecules inhibiting TGFb1 might represent a novel strategy for improving current immunotherapies.