Inhibition of RNA-binding proteins enhances immunotherapy in ovarian cancer

Area of Science:

• Oncology
• Immunology
• Molecular Biology

Background:

• High-grade serous ovarian cancer (HGSC) has poor outcomes, with the C5 subtype characterized by immune evasion.
• The molecular mechanisms underlying the C5 subtype's 'immune desert' phenotype are poorly understood.

Purpose of the Study:

• To identify key regulators of immune evasion in C5-HGSC.
• To elucidate the role of RNA-binding proteins (RBPs) in C5-HGSC immune evasion.
• To explore therapeutic strategies targeting RBPs in C5-HGSC.

Main Methods:

• Integrated single-cell and bulk RNA sequencing to identify RBPs.
• Loss-of-function screens in C5-like cell models.
• In vitro and in vivo studies assessing IGF2BP1 function.
• Mechanistic studies on interferon-gamma signaling and MHC-I presentation.
• Therapeutic evaluation of IGF2BP1 inhibition (BTYNB) combined with PD-1 blockade.
• Multi-spectral imaging of human HGSC tissues.

Main Results:

• RNA-binding proteins (RBPs) are identified as key regulators of immune evasion in C5-HGSC.
• IGF2BP1 is a central mediator, suppressing interferon-gamma signaling by accelerating IRF1 degradation, thus impairing MHC-I presentation.
• IGF2BP1 decouples PD-L1 expression and limits immune cell infiltration and T cell activation.
• The small molecule BTYNB inhibits IGF2BP1 and synergizes with PD-1 blockade to overcome immune evasion in vivo.
• Oncofetal RBPs are confirmed as drivers of the C5-HGSC subtype.

Conclusions:

• A novel RBP-interferon regulatory axis is uncovered in C5-HGSC.
• IGF2BP1 inhibition represents a promising therapeutic strategy to enhance immune checkpoint therapy in immunologically cold ovarian tumors.