DDX3 regulates cancer immune surveillance via 3' UTR-mediated cell-surface expression of PD-L1

Cell Rep. 2024 Mar 26;43(3):113937. doi: 10.1016/j.celrep.2024.113937. Epub 2024 Mar 13.

Abstract

Programmed death-1 (PD-1)/PD ligand-1 (PD-L1)-mediated immune escape contributes to cancer development and has been targeted as an anti-cancer strategy. Here, we show that inhibition of the RNA helicase DDX3 increased CD8+ T cell infiltration in syngeneic oral squamous cell carcinoma tumors. DDX3 knockdown compromised interferon-γ-induced PD-L1 expression and, in particular, reduced the level of cell-surface PD-L1. DDX3 promoted surface PD-L1 expression by recruiting the adaptor protein 2 (AP2) complex to the 3' UTR of PD-L1 mRNA. DDX3 depletion or 3' UTR truncation increased the binding of the coatomer protein complexes to PD-L1, leading to its intracellular accumulation. Therefore, this 3' UTR-dependent mechanism may counteract cellular negative effects on surface trafficking of PD-L1. Finally, pharmaceutic disruption of DDX3's interaction with AP2 reduced surface PD-L1 expression, supporting that the DDX3-AP2 pathway routes PD-L1 to the cell surface. Targeting DDX3 to modulate surface trafficking of immune checkpoint proteins may provide a potential strategy for cancer immunotherapy.

Keywords: 3’ UTR-mediated protein-protein interaction; CP: Cancer; CP: Immunology; YXXØ; sorting motif.

MeSH terms

  • 3' Untranslated Regions / genetics
  • B7-H1 Antigen / metabolism
  • CD8-Positive T-Lymphocytes
  • Carcinoma, Squamous Cell* / metabolism
  • Humans
  • Mouth Neoplasms* / genetics

Substances

  • 3' Untranslated Regions
  • B7-H1 Antigen