FOXP1 suppresses immune response signatures and MHC class II expression in activated B-cell-like diffuse large B-cell...

Area of Science:

• Hematology
• Immunology
• Molecular Biology

Background:

• The transcription factor FOXP1 (forkhead box P1) is recognized as a marker of poor prognosis in diffuse large B-cell lymphoma (DLBCL).
• DLBCL is categorized into germinal center B-cell (GCB)-like and activated B-cell (ABC)-like subtypes, exhibiting distinct molecular and clinical features.
• FOXP1 exhibits differential expression and isoform usage between these DLBCL subtypes.

Purpose of the Study:

• To investigate the role of FOXP1 in regulating immune response signatures and major histocompatibility complex class II (MHC II) genes in DLBCL.
• To determine the correlation between FOXP1 expression, MHC II gene expression, and clinical outcomes in DLBCL patients.
• To explore the potential of targeting the FOXP1 pathway for therapeutic benefit in DLBCL.

Main Methods:

• Microarray analysis of FOXP1-silenced DLBCL cell lines to identify differentially regulated genes.
• Analysis of independent primary DLBCL microarray data sets to correlate FOXP1 and MHC II gene expression.
• FOXP1 knockdown experiments in ABC-DLBCL cells to assess cell-surface protein expression.
• Retrospective analysis of FOXP1 and HLA-DRA expression in R-CHOP-treated DLBCL patients (n=150) and correlation with survival and subtype.

Main Results:

• FOXP1 silencing significantly altered immune response signatures and MHC II gene expression in DLBCL cell lines.
• Multiple MHC II genes, including HLA-DRA, were inversely correlated with FOXP1 transcript levels in primary DLBCL.
• FOXP1 knockdown increased cell-surface HLA-DRA and CD74 expression in ABC-DLBCL cells.
• Reduced HLA-DRA expression (<90%) in R-CHOP-treated patients correlated with inferior overall and progression-free survival and non-GCB subtype.
• In non-GCB DLBCL, reduced HLA-DRA correlated inversely with FOXP1 expression frequency and intensity.

Conclusions:

• FOXP1 is a novel regulator of CIITA-targeted genes, including MHC II and CD74, in DLBCL.
• FOXP1 expression levels and its regulation of MHC II genes are critical determinants of DLBCL prognosis.
• Targeting the FOXP1 pathway may enhance antigen presentation and immune surveillance, offering a potential therapeutic strategy for high-risk DLBCL.