MAP4K2 suppresses antitumor immunity in a pancreatic cancer model by promoting Treg differentiation.

MAP kinase kinase kinase kinase (MAP4K) family kinases are key kinases for T cell-mediated immune responses; however, in vivo roles of MAP4K2 in immune regulation remain unclear. Using T cell-specific Map4k2 conditional knockout (T-Map4k2 cKO) mice, scRNA-seq, and mass spectrometry analysis, we found that MAP4K2 interacted with DDX39B, induced forkhead box protein P3 (FOXP3) gene expression, and promoted Treg differentiation. Mechanistically, MAP4K2 directly phosphorylated the DEAD box protein DDX39B, leading to DDX39B nuclear translocation and subsequent Foxp3 RNA splicing. MAP4K2-induced FOXP3 mRNA levels were abolished in DDX39B knockout T cells. Furthermore, T-Map4k2 cKO mice displayed the reduction of Treg population and the sustained inflammation during remission phase of EAE autoimmune disease model. Remarkably, the anti-PD-1 immunotherapeutic effect on pancreatic cancer was significantly improved in T-Map4k2 cKO mice, Treg-specific Map4k2-deficient mice, adoptively transferred chimeric mice, or MAP4K2-inhibitor-treated mice. Consistently, scRNA-seq analysis of patients with pancreatic cancer showed increased MAP4K2 levels in infiltrating Treg cells. Collectively, MAP4K2 promotes Treg differentiation by inducing DDX39B nuclear translocation, leading to the attenuation of antitumor immunity.