METTL16 promotes PD-L1 expression and mediates immunosuppression in B-cell lymphomas via m6A methylation.
OBJECTIVES Immune Checkpoint Inhibitors (ICIs) have changed cancer treatment. Altered expression of methyltransferase-like 16 (METTL16), one of the initial m6A "writers", is associated with malignant progression. METTL16 is a methyltransferase that may influence the treatment response of B-cell lymphoma (BCL). METHODS Overexpression and knockdown strategies were used to regulate METTL16 expression in BCL cells, and then qPCR and western blot were employed to measure the levels of METTL16 and programmed death ligand 1 (PD-L1). A BCL-T cell co-culture system was employed to study immune evasion. T cell activation and infiltration into tumor and spleen tissues were assessed by flow cytometry. METTL16 function in regulating the m6A modification of PD-L1 mRNA was explored by MeRIP and RNA stability assays. Using a xenograft mouse model, we determined that METTL16 promotes BCL tumor growth. RESULTS Silencing METTL16 in BCL cells inhibited their proliferation and reduced neoplastic expansion in vivo. METTL16 silencing enhanced T cell activation and cytokine release. METTL16 promoted the association of Insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) and PD-L1 mRNA by regulating m6A modification. Reduction of METTL16 in BCL cells led to a lower proportion of PD-1-positive T cells in the co-culture system. In addition, an increase in METTL16 elevated the resistance of BCL cancer to inhibition by anti-PD-L1 therapy. CONCLUSION Our findings indicate that METTL16 promotes BCL progression and immune evasion through epigenetic regulation of the PD-L1/PD-1 pathway.