High-dimensional mass cytometry analysis of NK cell alterations in AML identifies a subgroup with adverse clinical outcome.

Natural killer (NK) cells are major antileukemic immune effectors. Leukemic blasts have a negative impact on NK cell function and promote the emergence of phenotypically and functionally impaired NK cells. In the current work, we highlight an accumulation of CD56CD16 unconventional NK cells in acute myeloid leukemia (AML), an aberrant subset initially described as being elevated in patients chronically infected with HIV-1. Deep phenotyping of NK cells was performed using peripheral blood from patients with newly diagnosed AML ( = 48, HEMATOBIO cohort, NCT02320656) and healthy subjects ( = 18) by mass cytometry. We showed evidence of a moderate to drastic accumulation of CD56CD16 unconventional NK cells in 27% of patients. These NK cells displayed decreased expression of NKG2A as well as the triggering receptors NKp30 and NKp46, in line with previous observations in HIV-infected patients. High-dimensional characterization of these NK cells highlighted a decreased expression of three additional major triggering receptors required for NK cell activation, NKG2D, DNAM-1, and CD96. A high proportion of CD56CD16 NK cells at diagnosis was associated with an adverse clinical outcome and decreased overall survival (HR = 0.13; = 0.0002) and event-free survival (HR = 0.33; = 0.018) and retained statistical significance in multivariate analysis. Pseudotime analysis of the NK cell compartment highlighted a disruption of the maturation process, with a bifurcation from conventional NK cells toward CD56CD16 NK cells. Overall, our data suggest that the accumulation of CD56CD16 NK cells may be the consequence of immune escape from innate immunity during AML progression.