title: A comprehensive analysis of primary acute myeloid leukemia identifies biomarkers predicting susceptibility to human allogeneic Vγ9Vδ2 T cells.
abstract: Allogeneic innate lymphocytes such as Vγ9Vδ2 T cells are attractive candidates for cancer immunotherapy as they provide MHC-unrestricted antitumor activity without clinical evidence for inducing graft-versus-host disease (GvHD). However, current cellular immunotherapy approaches lack predictive biomarkers identifying patient cohorts most susceptible to immune attack. For this purpose we performed a comprehensive analysis of clinical, genetic, metabolic, and immunophenotypic features of 19 primary acute myeloid leukemia (AML) samples and correlated these factors with AML blast recognition by allogeneic Vγ9Vδ2 T cells. We show that 36% of primary AML samples were intrinsically susceptible to allogeneic Vγ9Vδ2 T cells. Among several evaluated features, only UL-16 binding protein 1 (ULBP1) expression (P<0.01) determines intrinsic AML susceptibility to allogeneic Vγ9Vδ2 T cells. Within the intrinsically resistant AML samples, pretreatment of AML blasts with nitrogen-containing bisphosphonates (NBP) significantly induced Vγ9Vδ2 T-cell cytotoxicity in 50% of AML samples, whereas 50% of AML samples were consistently refractory to γδ T-cell cytolysis. Activity of the mevalonate pathway (P<0.05) and myelomonocytic differentiation of AML (P<0.05) correlated with sensitivity of primary AML samples toward NBP pretreatment. In conclusion, this study identifies subsets of AML patients most likely to benefit from allogeneic Vγ9Vδ2 T-cell-mediated immunotherapy.
authors.affiliation: *Medizinische Klinik und Poliklinik II †Institut für Klinische Transfusionsmedizin und Hämotherapie, University of Würzburg, Würzburg §Medizinische Klinik V, Klinikum Nürnberg Nord, Nürnberg, Germany ‡Baker IDI Heart and Diabetes Institute, Melbourne, Vic., Australia.
authors.forename: Stefan
authors.initials: S
authors.lastname: Gundermann
authors.forename: Erdwine
authors.initials: E
authors.lastname: Klinker
authors.forename: Brigitte
authors.initials: B
authors.lastname: Kimmel
authors.forename: Ulrike
authors.initials: U
authors.lastname: Flierl
authors.forename: Martin
authors.initials: M
authors.lastname: Wilhelm
authors.forename: Hermann
authors.initials: H
authors.lastname: Einsele
authors.forename: Volker
authors.initials: V
authors.lastname: Kunzmann
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002478:Cells, Cultured; D003602:Cytotoxicity, Immunologic; D005260:Female; D058851:GPI-Linked Proteins / Q000378:metabolism; D020544:Graft vs Leukemia Effect / Q000276:immunology; D006680:HLA Antigens / Q000276:immunology; D006648:Histocompatibility; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000379:methods*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D015470:Leukemia, Myeloid, Acute / Q000175:diagnosis* / Q000276:immunology / Q000628:therapy*; D008297:Male; D008875:Middle Aged; D011237:Predictive Value of Tests; D011379:Prognosis; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology* / Q000637:transplantation; D014184:Transplantation, Homologous
chemical_list: D058851:GPI-Linked Proteins; D006680:HLA Antigens; D047908:Intracellular Signaling Peptides and Proteins; D016692:Receptors, Antigen, T-Cell, gamma-delta; C521523:T-cell receptor Vdelta2, human; C521522:T-cell receptor Vgamma9, human; C423231:ULBP1 protein, human