Interleukin-15 enhanced the survival of human γδT cells by regulating the expression of Mcl-1 in neuroblastoma

Neuroblastoma (NB) is the most common extracranial solid tumor and the treatment efficacy of high-risk NB is unsatisfactory. γδT-cell-based adoptive cell transfer is a promising approach for high-risk NB treatment. Our previous study has revealed that γδT cells in NB patients exhibit a poor proliferation activity and a decreased anti-tumor capacity in vitro. In the present study, we found that IL-15 could effectively enhance the proliferation of NB γδT cells, to a level that remains lower than healthy controls though. In addition, IL-15-fostered NB γδT cells robustly boosted cell survival against apoptosis induced by cytokines depletion. Our data revealed that Mcl-1 was a key anti-apoptotic protein in IL-15-fostered γδT cells during cytokine withdrawal and its expression was regulated via the activation of STAT5 and ERK. In addition, IL-2 and IL-15-fostered γδT cells harbored higher levels of tumoricidal capacity which is also beneficial for γδ T-cell based immune therapy in NB. Understanding the survival control of γδT cells in a sub-optimal cytokine supportive microenvironment will expedite the clinical application of γδT cells for immunotherapy.