TH1 cytokines induce senescence in AML. (June 2022)

• Record Type: Journal Article
• Authors: Hashimoto, Hisayoshi; Güngör, Derya; Krickeberg, Naomi; Schmitt, Johanna; Doll, Larissa; Schmidt, Marina; Schleicher, Sabine; Criado-Moronati, Elvira; Schilbach, Karin
• Is Part Of: Leukemia research. Volume 117(2022)
• Publication Date: 2022-06
• Subjects: AML -- Senescence induction -- TH1 cytokines -- Combined IFN-γ+ and TNF-α+ -- PRAME -- CD4+ T cells -- Virus-specific T cells -- γδT cells; Leukemia -- Periodicals; Leukemia -- Periodicals; Leucémie -- Périodiques; Leukemia; Periodicals; Electronic journals; Electronic journals; 616.9941905
• DOI: 10.1016/j.leukres.2022.106842
• Languages: English
• ISSNs: 0145-2126

Abstract

Abstract: Cancer testis antigen PRAME is over-expressed in a variety of malignant cells but is not or minimally expressed in normal non-germ line cells. Adoptive transfer of PRAME-specific T cells is thus under investigation in clinical trials as an innovative therapeutic option for acute myeloid leukemia (AML). However, their senescence-inducing activity has not been studied. This study therefore examines senescence induction in AML cells by PRAME-specific TH 1 cells. Analysis of cell cycle and marker expression demonstrate that the supernatants of antigen-stimulated PRAME-specific TH 1 cells induce senescence in AML cell lines Kasumi and Nomo-1 through combinative IFN-γ and TNF-α. Additionally IFN-γ and TNF-α secreted by TCR-activated Vδ2 + or CMV-specific T cells can also drive these AML cell lines into terminal growth arrest. G1/0 arrest is also suggested in patient-derived AML by TH 1 cytokines or supernatants from Zoledronate-stimulated or aCD3/aCD28-stimulated PBMCs. Thus, we show for the first time that senescence is induced in AML cells by combined IFN-γ and TNF-α, and that these cytokines can be derived either from TCR-engineered CD4 + T cells, or intriguingly from Virus-specific as well as innate Vδ2 + T cells responding to their cognate antigens, namely T-cell responses targeting an antigen that is NOT expressed by the leukemic cells. Graphical Abstract: ga1 Highlights: TH 1 cytokines IFN-γ and TNF-α combined induce senescence in acute myeloid leukemia. IFN-γ/TNF-α from any TH 1 cell responding to its cognate antigen can induce senescence. Sensitivity for senescence induction by TNF-α/IFN-γ occurs in physiologic concentrations ranging over more than 2 log phases.