title: Profiles of activation, differentiation-markers, or β-integrins on T cells contribute to predict T cells' antileukemic responses after stimulation with leukemia-derived dendritic cells.
abstract: Stem cell transplantations and donor lymphocyte infusions are promising immunotherapies to cure acute myeloid leukemia (AML). Leukemia-derived dendritic cells are known to improve antileukemic functionality of T cells. We evaluated the composition and development of distinct T-cell subtypes in AML patients (n=12) compared with healthy probands (n=5) before and during stimulation with leukemia-derived dendritic cells-containing DC (DC) or blast-containing mononuclear cells (MNC) in 0-7 days mixed lymphocyte cultures (MLC) by flow cytometry. AML patients' T-cell subgroups were correlated with antileukemic functionality before and after DC/MNC stimulation by functional fluorolysis assays. (1) Unstimulated T cells from AML patients presented with significantly lower proportions of activated, Tcm, CD137, and β-integrin T cells, and significantly higher proportions of Tnaive and Teff compared with healthy probands. (2) After 7 days of DC or MNC stimulation, T-cell profiles were characterized by (significantly) increased proportions of activated T cells with effector function and significantly decreased proportions of β-integrin T cells. (3) Antileukemic cytotoxicity was achieved in 40% of T cells after MNC stimulation compared with 64% after DC stimulation. Antileukemic activity after DC stimulation but not after MNC stimulation correlated with higher proportions of Tcm and Tnaive before stimulation, as well as with significantly higher proportions of activated and β-integrin T cells. Furthermore, cutoff values for defined T-cell activation/differentiation markers and β-integrin T cells could be defined, allowing a prediction of antileukemic reactivity. We could demonstrate the potential of the composition of unstimulated/DC-stimulated T cells for the lysis of AML blasts. Especially, AML patients with high numbers of Tnaive and Tcm could benefit from DC stimulation; proportions of activated and β-integrin T cells correlated with increased antileukemic functionality and could serve to predict T cells' reactivity during stimulation. Refined analyses in the context of responses to immunotherapies are required.
authors.affiliation: *Department for Hematopoetic Cell Transplantations, University Hospital of Munich †Helmholtz Center Munich (German Research Center for Environmental Health and Clinical Cooperative Group Hematopoetic Cell-Transplantation), Munich ‡Department for Hematology and Oncology, Municipal Hospital, Oldenburg, Germany.
authors.forename: Valentin
authors.initials: V
authors.lastname: Vogt
authors.forename: Julia
authors.initials: J
authors.lastname: Schick
authors.forename: Christian
authors.initials: C
authors.lastname: Ansprenger
authors.forename: Marion
authors.initials: M
authors.lastname: Braeu
authors.forename: Tanja
authors.initials: T
authors.lastname: Kroell
authors.forename: Doris
authors.initials: D
authors.lastname: Kraemer
authors.forename: Claus-Henning
authors.initials: CH
authors.lastname: Köhne
authors.forename: Andreas
authors.initials: A
authors.lastname: Hausmann
authors.forename: Raymund
authors.initials: R
authors.lastname: Buhmann
authors.forename: Johanna
authors.initials: J
authors.lastname: Tischer
authors.forename: Helga
authors.initials: H
authors.lastname: Schmetzer
mesh_terms: D000328:Adult; D000368:Aged; D017951:Antigen Presentation; D000943:Antigens, Differentiation / Q000378:metabolism; D000951:Antigens, Neoplasm / Q000276:immunology; D019496:Cancer Vaccines; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology* / Q000637:transplantation; D005260:Female; D006801:Humans; D016130:Immunophenotyping; D016219:Immunotherapy, Adoptive / Q000379:methods*; D039641:Integrin beta Chains / Q000378:metabolism; D015470:Leukemia, Myeloid, Acute / Q000175:diagnosis* / Q000276:immunology / Q000628:therapy*; D008213:Lymphocyte Activation; D008297:Male; D008875:Middle Aged; D011237:Predictive Value of Tests; D011379:Prognosis; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D000943:Antigens, Differentiation; D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; D039641:Integrin beta Chains