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

Area of Science:

• Immunology
• Molecular Biology
• Cell Biology

Background:

• MAP kinase kinase kinase kinase (MAP4K) family kinases are vital for T-cell immunity.
• The specific in vivo role of MAP4K2 in immune regulation is not fully understood.

Purpose of the Study:

• To elucidate the in vivo function of MAP4K2 in immune regulation.
• To investigate the mechanism by which MAP4K2 influences T regulatory cell (Treg) differentiation.

Main Methods:

• Utilized T-cell-specific Map4k2 conditional knockout (T-Map4k2 cKO) mice.
• Employed single-cell RNA sequencing (scRNA-seq) and mass spectrometry.
• Investigated protein interactions and phosphorylation events.

Main Results:

• MAP4K2 interacts with DDX39B and promotes forkhead box protein P3 (FOXP3) gene expression, driving Treg differentiation.
• MAP4K2 directly phosphorylates DDX39B, facilitating its nuclear translocation and subsequent FOXP3 RNA splicing.
• T-Map4k2 cKO mice showed reduced Treg populations, sustained inflammation in an EAE model, and enhanced anti-PD-1 immunotherapy efficacy for pancreatic cancer.

Conclusions:

• MAP4K2 is a key regulator of Treg differentiation via the DDX39B pathway.
• MAP4K2 inhibition or deficiency can attenuate Treg-mediated suppression, improving antitumor immunity.
• Elevated MAP4K2 levels in tumor-infiltrating Treg cells of pancreatic cancer patients suggest its clinical relevance.