TH1 cytokines induce senescence in AML

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 T_H1 cells. Analysis of cell cycle and marker expression demonstrate that the supernatants of antigen-stimulated PRAME-specific T_H1 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 T_H1 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.

Keywords: AML; CD4(+) T cells; Combined IFN-γ(+) and TNF-α(+); PRAME; Senescence induction; T(H)1 cytokines; Virus-specific T cells; γδT cells.