Cancer patient outcomes correlate with activating-KIR/ligand repertoires associated with distinct NK cell transcriptomic profiles
4 affiliations
- 1Immunology Service, Virgen de la Arrixaca University Clinical Hospital (HCUVA), Biomedical Research Institute of Murcia (IMIB), Murcia, Spain
- 2School of Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, UK
- 3Urology Service, Virgen de la Arrixaca University Clinical Hospital (HCUVA), Biomedical Research Institute of Murcia (IMIB), Murcia, Spain
- 4Human Anatomy Department, Universidad de Murcia and Campus Mare Nostrum, Biomedical Research Institute of Murcia (IMIB), Murcia, Spain
Abstract
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 KIR and HLA-I genotyping, together with KIR expression analysis in circulating NK cells, were performed in patients with solid and hematologic malignancies (n = 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.
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BibTeX
@article{ruizlorente2026cancer,
title = {{Cancer patient outcomes correlate with activating-KIR/ligand repertoires associated with distinct NK cell transcriptomic profiles}},
author = {Inmaculada Ruiz-Lorente and Andrés Vallejo-Pulido and Alicia López-Abad and Pedro López Cubillana and Víctor Barozi and Salim I. Khakoo and Alfredo Minguela and Lourdes Gimeno},
journal = {OncoImmunology},
year = {2026},
month = nov,
doi = {10.1080/2162402x.2026.2756722},
url = {https://doi.org/10.1080/2162402x.2026.2756722},
note = {CC BY},
}
RIS
TY - JOUR
TI - Cancer patient outcomes correlate with activating-KIR/ligand repertoires associated with distinct NK cell transcriptomic profiles
AU - Inmaculada Ruiz-Lorente
AU - Andrés Vallejo-Pulido
AU - Alicia López-Abad
AU - Pedro López Cubillana
AU - Víctor Barozi
AU - Salim I. Khakoo
AU - Alfredo Minguela
AU - Lourdes Gimeno
PY - 2026
DA - 2026/11/04
JO - OncoImmunology
DO - 10.1080/2162402x.2026.2756722
UR - https://doi.org/10.1080/2162402x.2026.2756722
AB - 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 KIR and HLA-I genotyping, together with KIR expression analysis in circulating NK cells, were performed in patients with solid and hematologic malignancies (n = 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.
SN - 2162-402X
ER -