Cancer patient outcomes correlate with activating-KIR/ligand repertoires associated with distinct NK cell transcriptomic profiles

BACKGROUND: Rates of cancer cure increase; however, recurrence and refractoriness remain clinical challenges that require alternative therapeutic strategies. Natural killer (NK) cells could play a decisive role if their antitumor reactivity can be enhanced. The interaction between killer-cell immunoglobulin-like receptors (KIRs) and their human leukocyte antigen class-I (HLA-I) ligands significantly influences NK-cell education and may impact clinical outcomes in cancer patients. In this study, we evaluated the impact of KIR/HLA-I interactions on the transcriptomic profile of circulating NK-cells and their association with patient outcome. METHODS: = 1,153). In addition, single-cell transcriptomic analyses (scRNA-seq) of circulating NK and T lymphocytes were carried out in selected donors with KIR/HLA-I genotypes associated with short and long survival. RESULTS: Activating KIRs (aKIRs), more than inhibitory KIRs, were associated with cancer patient outcomes. The accumulation of aKIR-HLA interactions was related to shorter overall survival, whereas KIR2DS1/C2 interaction, in the absence of other aKIR interactions, was associated with longer survival. Three major NK-cell transcriptional profiles were identified: mature cytotoxic, immature/regulatory, and adaptive cytotoxic. The adaptive-like transcriptional profile was associated with longer survival. CONCLUSIONS: In conclusion, aKIR/HLA-I interactions were associated with cancer patient outcomes. In particular, KIR2DS1/C2 interaction in the absence of other activating signals was associated with adaptive NK-cell transcriptomic profiles and improved survival. Understanding the mechanisms underlying effective NK-cell-mediated tumor immunity may provide new opportunities for patients with refractory tumors.