2. Academic Validation
  3. Kunitz-type protease inhibitor TFPI2 remodels stemness and immunosuppressive tumor microenvironment in glioblastoma

Kunitz-type protease inhibitor TFPI2 remodels stemness and immunosuppressive tumor microenvironment in glioblastoma

  • Nat Immunol. 2023 Sep 4. doi: 10.1038/s41590-023-01605-y.
Lizhi Pang # 1,  Madeline Dunterman # 1,  Songlin Guo 1,  Fatima Khan 1,  Yang Liu 1,  Erfan Taefi 2,  Atousa Bahrami 2,  Changiz Geula 2,  Wen-Hao Hsu 3,  Craig Horbinski 1 4,  Charles David James 1,  Peiwen Chen 5
Affiliations

Affiliations

  • 1 Department of Neurological Surgery, Lou and Jean Malnati Brain Tumor Institute, Robert H Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
  • 2 Mesulam Center for Cognitive Neurology and Alzheimer's Disease; Department of Cell and Developmental Biology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
  • 3 Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 4 Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
  • 5 Department of Neurological Surgery, Lou and Jean Malnati Brain Tumor Institute, Robert H Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA. peiwen.chen@northwestern.edu.
  • # Contributed equally.
PMID: 37667051 DOI: 10.1038/s41590-023-01605-y
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.

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