Reviving human γδT cells from apoptosis induced by IL-12/18 via p-JNK inhibition

Abstract γδT cells recognize and exert cytotoxicity against tumor cells independently of MHC restriction and have antigen presentation and regulatory functions to promote adaptive immune responses. They are considered as potential immune cells for cellular immunotherapy in cancer patients. However, it is challenging to ex vivo expand human γδT cells that have superb effector functions and long-term survival for adoptive cancer therapy. We found that IL-12/18 combination could drastically promote IFN-γ secretion and cytotoxicity in human γδT cells. However, the enhanced activation of human γδT cells is accompanied by increased apoptosis and elevated expressions of co-inhibitory receptors under the stimulation of IL-12/18. We further demonstrated that IL-12/18 induced apoptosis of human γδT cells was in a phosphoantigen or IFN-γ-independent manner. Transcriptomic analysis suggested that IL-12/18-induced apoptosis of human γδT cells was mediated by the activation of JNK pathway. p-JNK inhibitor (SP-600125) treatment effectively revived human γδT cells from the apoptosis induced by IL-12/18 and maintained their enhanced IFN-γ production and cytotoxicity against tumor cells. Our results provide a novel and feasible strategy for ex vivo expansion of cytokine-activated human γδT cells, which could promote the efficacy of γδT cell adoptive immunotherapy in cancer patients.