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

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*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

24 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1654-1670
Number of pages17
JournalNature Immunology
Volume24
Issue number10
DOIs
StatePublished - Oct 2023

Funding

We thank S. D. Rabkin, F. Lang, J. Hu and H. Okada for providing 005 GSCs, patient-derived GSCs, QPP7 GSC and SB28, respectively. This work was supported in part by NIH R00 CA240896 (P.C.), NIH R01 NS124594 (P.C.), DoD Career Development Award W81XWH-21-1-0380 (P.C.), Cancer Research Foundation Young Investigator Award (P.C.), Lynn Sage Scholar Award (P.C.), American Cancer Society Institutional Research Grant IRG-21-144-27 (P.C.), NIH P50 CA221747 (to P.C., Brain Cancer SPORE CEP Award), philanthropic donation from Mindy Jacobson and the Bill Bass Foundation (P.C.), Northwestern University start-up funds (P.C.), the Northwestern Medicine Malnati Brain Tumor Insitute of the Robert H. Lurie Comprehensive Cancer Center (P.C.), NIH R24 NS104160 (C.G.) and NIH P30 AG072977 (C.G.). W.H.H. is funded by the CPRIT Training Program (RP210028). Imaging work was performed at the Northwestern University Center for Advanced Microscopy generously supported by NCI CCSG P30 CA060553. Proteomics experiments were performed at the Northwestern Proteomics Core Facility, which is generously supported by NCI CCSG P30 CA060553, instrumentation award (S10OD025194) from NIH Office of Director, and P41 GM108569. Incucyte analysis was performed in the Analytical bioNanoTechnology Core (ANTEC) Facility supported by the Soft and Hybrid Nanotechnology Experimental (SHyNE) Resource (NSF ECCS-2025633).

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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