High-dimensional single-cell analysis of human natural killer cell heterogeneity

Natural killer (NK) cells are innate lymphoid cells (ILCs) contributing to immune responses to microbes and tumors. Historically, their classification hinged on a limited array of surface protein markers. Here, we used single-cell RNA sequencing (scRNA-seq) and cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq) to dissect the heterogeneity of NK cells. We identified three prominent NK cell subsets in healthy human blood: NK1, NK2 and NK3, further differentiated into six distinct subgroups. Our findings delineate the molecular characteristics, key transcription factors, biological functions, metabolic traits and cytokine responses of each subgroup. These data also suggest two separate ontogenetic origins for NK cells, leading to divergent transcriptional trajectories. Furthermore, we analyzed the distribution of NK cell subsets in the lung, tonsils and intraepithelial lymphocytes isolated from healthy individuals and in 22 tumor types. This standardized terminology aims at fostering clarity and consistency in future research, thereby improving cross-study comparisons

High-dimensional single-cell analysis of human natural killer cell heterogeneity.

Natural killer (NK) cells are innate lymphoid cells (ILCs) contributing to immune responses to microbes and tumors. Historically, their classification hinged on a limited array of surface protein markers. Here, we used single-cell RNA sequencing (scRNA-seq) and cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq) to dissect the heterogeneity of NK cells. We identified three prominent NK cell subsets in healthy human blood: NK1, NK2 and NK3, further differentiated into six distinct subgroups. Our findings delineate the molecular characteristics, key transcription factors, biological functions, metabolic traits and cytokine responses of each subgroup. These data also suggest two separate ontogenetic origins for NK cells, leading to divergent transcriptional trajectories. Furthermore, we analyzed the distribution of NK cell subsets in the lung, tonsils and intraepithelial lymphocytes isolated from healthy individuals and in 22 tumor types. This standardized terminology aims at fostering clarity and consistency in future research, thereby improving cross-study comparisons

High-dimensional single-cell analysis of human natural killer cell heterogeneity.

Funder: E.V laboratory at CIML and Assistance-Publique des Hôpitaux de Marseille is supported by funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation program (TILC, grant agreement No. 694502 and MInfla-TILC, grand agreement No. 875102), the Agence Nationale de la Recherche including the PIONEER Project (ANR-17-RHUS-0007), MSDAvenir, Innate Pharma and institutional grants awarded to the CIML (INSERM, CNRS and Aix-Marseille University) and Marseille Immunopole.Funder: D.M.D laboratory is funded by the Medical Research Council (MR/W031698/1) and the Wellcome Trust (110091/Z/15/Z).Funder: A.D. laboratory is supported by the European Research Council (ERC AdG ILCAdapt, 101055309 to A.D.) and by the German Research Foundation (DFG) (SFB 1444/427826188 and TRR 241/375876048 to A.D., SPP1937/Di764 /9-2 to A.D.). We are grateful to the Benjamin Franklin Flow Cytometry Facility (BFFC) for support in cell sorting. BFFC is supported by DFG Instrument Grants INST 335/597-1 FUGG und INST 335/777-1 FUGG.Funder: KJM was supported by the Research Council of Norway, Center of Excellence: Precision Immunotherapy Alliance (332727), the US National Cancer Institute (P01 CA111412, P009500901).Funder: L.M. is funded by Associazione Italiana contro il Cancro (AIRC), 5xmille project n. 21147.Funder: C.R. laboratory is supported by the ERC Advanced Grant ‘MEM-CLONK’ (101055157) and the Deutsche Forschungsgemeinschaft (DFG) grants SFB TRR241 B02 and RO 3565/7-1.Funder: D.G.R is supported by funding from the Medical Research Council (MRC) (MC_UU_00028) and Wellcome Trust-Academy of Medical Sciences (WT-AMS) (SBF009\1119).Funder: S.S. is funded by Ministero dell’Istruzione, dell’Università e della Ricerca: PRIN 2017WC8499_004 and Fondazione AIRC: AIRC 5×1000 project id. 21147.Natural killer (NK) cells are innate lymphoid cells (ILCs) contributing to immune responses to microbes and tumors. Historically, their classification hinged on a limited array of surface protein markers. Here, we used single-cell RNA sequencing (scRNA-seq) and cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq) to dissect the heterogeneity of NK cells. We identified three prominent NK cell subsets in healthy human blood: NK1, NK2 and NK3, further differentiated into six distinct subgroups. Our findings delineate the molecular characteristics, key transcription factors, biological functions, metabolic traits and cytokine responses of each subgroup. These data also suggest two separate ontogenetic origins for NK cells, leading to divergent transcriptional trajectories. Furthermore, we analyzed the distribution of NK cell subsets in the lung, tonsils and intraepithelial lymphocytes isolated from healthy individuals and in 22 tumor types. This standardized terminology aims at fostering clarity and consistency in future research, thereby improving cross-study comparisons

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Immunodynamics of explanted human tumors for immuno-oncology

International audienceDecision making in immuno-oncology is pivotal to adapt therapy to the tumor microenvironment (TME) of the patient among the numerous options of monoclonal antibodies or small molecules. Predicting the best combinatorial regimen remains an unmet medical need. Here, we report a multiplex functional and dynamic immuno-assay based on the capacity of the TME to respond to ex vivo stimulation with twelve immunomodulators including immune checkpoint inhibitors (ICI) in 43 human primary tumors. This "in sitro" (in situ/in vitro) assay has the potential to predict unresponsiveness to anti-PD-1 mAbs, and to detect the most appropriate and personalized combinatorial regimen. Prospective clinical trials are awaited to validate this in sitro assay