Kunitz-Type Protease Inhibitor TFPI2 Remodels Stemness and Immunosuppressive Tumor Microenvironment in Glioblastoma

Authors

Lizhi Pang
Madeline Dunterman
Songlin Guo
Fatima Khan
Yang Liu
Erfan Taefi
Atousa Bahrami
Changiz Geula
Wen-Hao Hsu
Craig Horbinski
Charles David James
Peiwen Chen

Publication Date

10-1-2023

Journal

Nature Immunology

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.

Keywords

Animals, Mice, Humans, Glioblastoma, Protease Inhibitors, Tumor Microenvironment, Signal Transduction, Carrier Proteins, Immunosuppressive Agents, Cell Line, Tumor, Neoplastic Stem Cells

DOI

10.1038/s41590-023-01605-y

PMID

37667051

PMCID

PMC10775912

PubMedCentral® Posted Date

10-1-2024

PubMedCentral® Full Text Version

Author MSS

Published Open-Access

yes