Abstract
Glioblastoma (GBM) tumors consist of multiple cell populations, including self-renewing glioblastoma stem cells (GSCs) and immunosuppressive microglia. Here we identified Kunitz-type protease inhibitor TFPI2 as a critical factor connecting these cell populations and their associated GBM hallmarks of stemness and immunosuppression. TFPI2 promotes GSC self-renewal and tumor growth via activation of the c-Jun N-terminal kinase-signal transducer and activator of transcription (STAT)3 pathway. Secreted TFPI2 interacts with its functional receptor CD51 on microglia to trigger the infiltration and immunosuppressive polarization of microglia through activation of STAT6 signaling. Inhibition of the TFPI2-CD51-STAT6 signaling axis activates T cells and synergizes with anti-PD1 therapy in GBM mouse models. In human GBM, TFPI2 correlates positively with stemness, microglia abundance, immunosuppression and poor prognosis. Our study identifies a function for TFPI2 and supports therapeutic targeting of TFPI2 as an effective strategy for GBM.
Overview
- The study investigates the role of Kunitz-type protease inhibitor TFPI2 in Glioblastoma (GBM) tumors. The study identifies TFPI2 as a critical factor connecting GSCs and immunosuppressive microglia and their associated GBM hallmarks of stemness and immunosuppression. The study aims to understand the mechanisms by which TFPI2 promotes GSC self-renewal and tumor growth via activation of the c-Jun N-terminal kinase-signal transducer and activator of transcription (STAT)3 pathway. The study also aims to investigate the role of TFPI2 in the infiltration and immunosuppressive polarization of microglia through activation of STAT6 signaling. The study aims to identify a function for TFPI2 and support therapeutic targeting of TFPI2 as an effective strategy for GBM.
Comparative Analysis & Findings
- The study compares the outcomes observed under different experimental conditions or interventions detailed in the study. The study identifies that TFPI2 promotes GSC self-renewal and tumor growth via activation of the c-Jun N-terminal kinase-signal transducer and activator of transcription (STAT)3 pathway. The study also identifies that TFPI2 interacts with its functional receptor CD51 on microglia to trigger the infiltration and immunosuppressive polarization of microglia through activation of STAT6 signaling. The study finds that inhibition of the TFPI2-CD51-STAT6 signaling axis activates T cells and synergizes with anti-PD1 therapy in GBM mouse models. The study also finds that TFPI2 correlates positively with stemness, microglia abundance, immunosuppression and poor prognosis in human GBM.
Implications and Future Directions
- The study's findings suggest that TFPI2 plays a critical role in GBM tumorigenesis and progression. The study identifies that TFPI2 promotes GSC self-renewal and tumor growth via activation of the c-Jun N-terminal kinase-signal transducer and activator of transcription (STAT)3 pathway. The study also identifies that TFPI2 interacts with its functional receptor CD51 on microglia to trigger the infiltration and immunosuppressive polarization of microglia through activation of STAT6 signaling. The study suggests that targeting the TFPI2-CD51-STAT6 signaling axis could be an effective strategy for GBM therapy. The study also identifies that TFPI2 correlates positively with stemness, microglia abundance, immunosuppression and poor prognosis in human GBM. Future research could further investigate the role of TFPI2 in GBM and explore its potential as a therapeutic target.