NK Cytotoxicity Mediated by NK-92 Cell Lines Expressing Combinations of Two Allelic Variants for <i>FCGR3</i>

Article Article scientifique Article NK Cytotoxicity Mediated by NK-92 Cell Lines Expressing Combinations of Two Allelic Variants for <i>FCGR3</i> eng 2024-07-12 2024-07-12 author Freitas Monteiro Marta Cristina Laboratory of Translational Immunology, Department of Medicine, Division of Immunology and Allergology, University Hospitals Geneva, Medical Faculty, CH-1211 Geneva, Switzerland. 861850 author Papaserafeim Maria Laboratory of Translational Immunology, Department of Medicine, Division of Immunology and Allergology, University Hospitals Geneva, Medical Faculty, CH-1211 Geneva, Switzerland. 758623 author Andreani Matteo Laboratory of Translational Immunology, Department of Medicine, Division of Immunology and Allergology, University Hospitals Geneva, Medical Faculty, CH-1211 Geneva, Switzerland. 411176 Département de médecine (DEMED) author Real Aline 0000-0002-9437-4411 Laboratory of Translational Immunology, Department of Medicine, Division of Immunology and Allergology, University Hospitals Geneva, Medical Faculty, CH-1211 Geneva, Switzerland. 893260 author Kouklas Athanasios 0000-0002-3282-0674 Laboratory of Translational Immunology, Department of Medicine, Division of Immunology and Allergology, University Hospitals Geneva, Medical Faculty, CH-1211 Geneva, Switzerland. 973449 author Reis Galvao Daniela Laboratory of Translational Immunology, Department of Medicine, Division of Immunology and Allergology, University Hospitals Geneva, Medical Faculty, CH-1211 Geneva, Switzerland. 971814 Département de médecine (DEMED) author Seebach Jorg Dieter 0000-0001-5748-4577 Laboratory of Translational Immunology, Department of Medicine, Division of Immunology and Allergology, University Hospitals Geneva, Medical Faculty, CH-1211 Geneva, Switzerland. 647894 Département de médecine (DEMED) author Puga Yung Gisella 0000-0002-2283-7798 Laboratory of Translational Immunology, Department of Medicine, Division of Immunology and Allergology, University Hospitals Geneva, Medical Faculty, CH-1211 Geneva, Switzerland. 666337 55 10.3390/antib13030055 39051331 2073-4468 PMC11270249 https://www.mdpi.com/2073-4468/13/3/55 Natural killer (NK) cells play an important role in the surveillance of viral infections and cancer. NK cell antibody-dependent cellular cytotoxicity (ADCC) and direct cytotoxicity are mediated by the recognition of antibody-coated target cells through the Fc gamma receptor IIIA (FcγRIIIa/CD16) and by ligands of activating/inhibitory NK receptors, respectively. Allelic variants of the FCGR3A gene include the high-affinity single-nucleotide polymorphism (SNP) rs396991 (V176F), which is associated with the efficacy of monoclonal antibody (mAb) therapies, and the SNP rs10127939 (L66H/R). The contribution of FCGR3A SNPs to NK cell effector functions remains controversial; therefore, we generated a panel of eight NK-92 cell lines expressing specific combinations of these SNPs and tested their cytotoxicities. NK-92 cells were stably transfected with plasmids containing different combinations of FCGR3A SNPs. Messenger RNA and FcγRIIIa/CD16 cell surface expressions were detected using new generation sequencing (NGS) and flow cytometry, respectively. All FcγRIIIa/CD16-transfected NK-92 cell lines exhibited robust ADCC against three different target cell lines with minor differences. In addition, enhanced direct NK cytotoxicity against K562 target cells was observed, suggesting a mechanistic role of FcγRIIIa/CD16 in direct NK cytotoxicity. In conclusion, we generated eight FcγRIIIa/CD16-transfected NK-92 cell lines carrying different combinations of two of the most studied FCGR3A SNPs, representing the major genotypes described in the European population. The functional characterization of these cell lines revealed differences in ADCC and direct NK cytotoxicity that may have implications for the design of adoptive cancer immunotherapies using NK cells and tumor antigen-directed mAbs. ADCC CD16 FCGR3A L48H/R L66H/R NK-92 V158F V176F Dewey 616 Swiss National Science Foundation Antibody-dependent innate immune cell functions in autoimmunity and monoclonal antibody therapies 201231 CH Projects Swiss National Science Foundation Xeno2Cure - advanced engineering and testing of organ donor pigs 198577 CH Programmes 56 Département de médecine 221 false 518 Cellules NK et récepteurs FcyR dans l'auto-immunité et le rejet de xénotransplantation 856 Antibodies 13 3 ed7ebcf7-d87e-4f9a-9704-ee215b2c0a82 Article (Published version) Public Article_scientifique_from_europePmc.pdf 4298177 application/pdf CC BY-4.0 ddeda82c3ebfa8e47479f5cfb3552ca9d627d811747b2f23bdbd701949c9b8e4 6936fb2d-06e4-4f3b-978d-9eda6c5c30bb Appendix Public antibodies-3001059-supplementary.pdf 935248 application/pdf 19aa7d6942ec733795c722e9b1b9335043f7fac6cc6af5a1c552f9155d353037 openAccess Faculté de médecine / Section de médecine clinique / Département de médecine

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Freitas Monteiro, Marta Cristina