Post-translational modification of cytoskeleton regulates anti-tumor cytotoxicity in γδ T cells

Abstract

Abstract γδ T cells based immunotherapy has emerged as a new treatment strategy for malignant tumors. The underlying cytotoxic mechanism against cancer cells involves surface receptor recognition molecules such as LFA-1, NKG2D, TRAIL, CD16, CD107a, and FasL, as well as cytokines such TNFα, IFNγ, perforin, and granzyme B. Previously, it has been shown that the cytoskeleton plays pivotal roles in T cell immunity. Nevertheless, the role of cytoskeleton in γδ T cell anti-tumor immunity remains largely unknown. In our work, we attempted to elucidate the functions of cytoskeleton in regulating the antitumor cytotoxicity of γδ T cells. We discovered that the acetylation of tubulin-α is positively correlated with γδ T cells cytotoxicity. While the down-regulation of tubulin-α acetylation in γδ T cells leads to decreased cancer cells killing efficacy, up-regulation could potentiate it through the expression of cytotoxic related molecules such as NKG2D, IFN-γ, CD16, and suppression of PD-1 molecule. Moreover, we observed that the acetylation of tubulin-α in γδ T cells drastically differs after challenged by MDA-MB-231, SkBr3, and MCF7 breast cancer cells, respectively, implying diverse γδ T cell immune responses towards these cell types. This result was further supported by the discrepancies in γδ T cell in vitro killing efficacy. Together, our work will provide important scientific references to further understand the cytoskeletal function in γδ T cell anti-tumor immunity.