High-grade serous ovarian cancer(HGSC)accounts for more than 70%of ovarian cancer-related deaths,yet therapeutic progress remains stagnant.Among the four molecular subtypes reported for HGSC,the C5 subtype is distingu...High-grade serous ovarian cancer(HGSC)accounts for more than 70%of ovarian cancer-related deaths,yet therapeutic progress remains stagnant.Among the four molecular subtypes reported for HGSC,the C5 subtype is distinguished by high proliferation and immune evasion with an unfavorable MHC-I/PD-L1 ratio.However,the molecular drivers of this immune desert state remain largely undefined.Here,we identify RNA-binding proteins(RBPs)as key regulators of immune evasion in C5-HGSC through integrated single-cell and bulk RNA sequencing.We perform a targeted loss-of-function screen in C5-like cell models and find IGF2BP1 as a central mediator of immune evasion in vitro and in vivo.Mechanistically,IGF2BP1 abrogates interferon-gamma signaling by accelerating IRF1 protein degradation,thereby suppressing MHC-I presentation.We also discover that IGF2BP1 decouples PD-L1 expression from IRF1-dependent transcription and reshapes the immune receptor landscape to limit immune cell infiltration and T cell activation.Therapeutically,the small-molecule BTYNB effectively inhibits IGF2BP1 and synergizes with PD-1 blockade to overcome immune evasion in vivo.Multi-spectral imaging confirms these findings in human HGSC tissues and highlights the role of oncofetal RBPs as molecular drivers of the C5-HGSC subtype.This subtype-wide survey uncovers a previously unrecognized RBP–interferon regulatory axis and establishes RBP inhibition as a therapeutic strategy to enhance immune checkpoint therapy in immunologically cold ovarian tumors.展开更多
基金supported by grants from the Deutsche Forschungsgemeinschaft(DFG)to Nadine Bley,Stefan Hüttelmaier,and Wolfgang Sippl(DFG-FOR5433,468534282)Nadine Bley and Stefan Hüttelmaier(DFG_GRK2751,449501615)+1 种基金The authors would like to thank Prof.Iain McNeish(Imperial College London,UK)for providing ID8 and ID8-TP53 knockout cell lines36 Furthermore,the authors would like to thank the Core Facility Imaging(CFI)providing all devices and technical support for imaging,FACS and flow cytometry as well as RNA sequencing,scRNA sequencing and data analyses.
文摘High-grade serous ovarian cancer(HGSC)accounts for more than 70%of ovarian cancer-related deaths,yet therapeutic progress remains stagnant.Among the four molecular subtypes reported for HGSC,the C5 subtype is distinguished by high proliferation and immune evasion with an unfavorable MHC-I/PD-L1 ratio.However,the molecular drivers of this immune desert state remain largely undefined.Here,we identify RNA-binding proteins(RBPs)as key regulators of immune evasion in C5-HGSC through integrated single-cell and bulk RNA sequencing.We perform a targeted loss-of-function screen in C5-like cell models and find IGF2BP1 as a central mediator of immune evasion in vitro and in vivo.Mechanistically,IGF2BP1 abrogates interferon-gamma signaling by accelerating IRF1 protein degradation,thereby suppressing MHC-I presentation.We also discover that IGF2BP1 decouples PD-L1 expression from IRF1-dependent transcription and reshapes the immune receptor landscape to limit immune cell infiltration and T cell activation.Therapeutically,the small-molecule BTYNB effectively inhibits IGF2BP1 and synergizes with PD-1 blockade to overcome immune evasion in vivo.Multi-spectral imaging confirms these findings in human HGSC tissues and highlights the role of oncofetal RBPs as molecular drivers of the C5-HGSC subtype.This subtype-wide survey uncovers a previously unrecognized RBP–interferon regulatory axis and establishes RBP inhibition as a therapeutic strategy to enhance immune checkpoint therapy in immunologically cold ovarian tumors.
