Adoptive transfer of IL‐4 reprogrammed Tc17 cells elicits anti‐tumour immunity through functional plasticity

Ability of IL‐17‐producing CD8+ T cells (Tc17) to transform into cytotoxic anti‐tumour effectors makes them a promising candidate for immune effector cell (IEC) therapy. However, key factors regulating Tc17 reprogramming remain poorly defined, hindering translation of Tc17‐based IEC use from bench to bedside. We probed the effects of multiple cytokines and underlying signalling pathways on Tc17 cells and identified pivotal role for IL‐4 and PI3K/AKT in promoting Tc17 transformation into cytotoxic IFN‐γ‐producing IECs, an effect dependent on Eomes expression. IL‐4 not only triggered Tc17 cytotoxicity, but also induced cell expansion, which significantly improved the antitumour potential of Tc17 cells compared to that of IFN‐γ‐producing CD8+ T cells (Tc1) in a murine model. Furthermore, IL‐4/AKT signalling drove the upregulation of the T‐cell receptor‐associated transmembrane adaptor 1 (Trat1) in Tc17 cells to promote IL‐4‐induced T‐cell receptor stabilization and Tc17 cytotoxicity. Finally, we proposed a possible procedure to expand human Tc17 from peripheral blood of cancer patients, and confirmed the function of IL‐4 in Tc17 reprogramming. Collectively, these results document a novel IL‐4/AKT/Eomes/Trat1 axis that promotes expansion and transformation of Tc17 cells into cytotoxic effectors with a therapeutic potential. IL‐4 priming of Tc17 cells should be further explored as a cell therapy engineering strategy to generate IECs to augment anti‐tumour responses. IL4 mediated Trat1 expression enhances Tc17 anti‐tumour phenotype. The IL‐4/AKT/Eomes/Trat1 axis is a novel signalling loop that promotes expansion and reprogramming of Tc17 cells into cytotoxic effectors with a therapeutic potential for adoptive cell transfer immunotherapy.