Brief IL-12, IL-15, IL-18 activation drives the acquisition of two distinct memory-like NK cell states

Abstract IL-12/15/18 activation induces natural killer (NK) cell differentiation into cytokine-induced memory-like (ML) NK cells with enhanced IFNγ and killing of tumor targets that is antigen independent, rendering them distinct from conventional (cNK) CMV-induced adaptive cells. In leukemia patients, ML have an excellent safety profile 47% CR rate (PMID: 32826231). Despite their clinical promise, little known about the biology underlying Based on individual variability human function, we hypothesized manifest molecular heterogeneity. To this end, applied Cellular Indexing Transcriptomes Epitopes by Sequencing (CITE-seq) to RNA protein expression single-cell level, evaluated function. Overnight stimulation induced broad transcriptional programs evident in CD56 brightcompared dimNK contrast, following vitrodifferentiation for 7 days, activated acquired a unique signature, one two states (ML-1, ML-2), or remained similar cNK ML-1 was marked increased activating receptor (NKp46, NKp30, NKp44) while ML-2 had inhibitory receptors, CD25, HLA-DR, MKI67, IFNG. functional assays, produced more cytokine than Further, divergent transcription factor profiles suggesting mechanisms regulation. Collectively, our findings reveal heterogeneity cells, investigations subsets patients receiving therapy are ongoing. AAI Intersect Fellowship Computational Scientists & Immunologists (JAF, TAF, AAP), T32GM139799 (JAF), P50CA171963 (TAF, MMB-E), R01CA205239 (TAF), P30CA91842 (TAF)