Hypoxia-driven protease legumain promotes immunosuppression in glioblastoma

Lizhi Pang; Songlin Guo; Fatima Khan; Madeline Dunterman; Heba Ali; Yang Liu; Yuyun Huang; Peiwen Chen

doi:10.1016/j.xcrm.2023.101238

Hypoxia-driven protease legumain promotes immunosuppression in glioblastoma

Lizhi Pang, Songlin Guo, Fatima Khan, Madeline Dunterman, Heba Ali, Yang Liu, Yuyun Huang, Peiwen Chen^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

29 Scopus citations

Abstract

Glioblastoma (GBM) is a hypoxic and “immune-cold” tumor containing rich stromal signaling molecules and cell populations, such as proteases and immunosuppressive tumor-associated macrophages (TAMs). Here, we seek to profile and characterize the potential proteases that may contribute to GBM immunosuppression. Legumain (LGMN) emerges as the key protease that is highly enriched in TAMs and transcriptionally upregulated by hypoxia-inducible factor 1-alpha (HIF1α). Functionally, the increased LGMN promotes TAM immunosuppressive polarization via activating the GSK-3β-STAT3 signaling pathway. Inhibition of macrophage HIF1α and LGMN reduces TAM immunosuppressive polarization, impairs tumor progression, enhances CD8⁺ T cell-mediated anti-tumor immunity, and synergizes with anti-PD1 therapy in GBM mouse models. Thus, LGMN is a key molecular switch connecting two GBM hallmarks of hypoxia and immunosuppression, providing an actionable therapeutic intervention for this deadly disease.

Original language	English (US)
Article number	101238
Journal	Cell Reports Medicine
Volume	4
Issue number	11
DOIs	https://doi.org/10.1016/j.xcrm.2023.101238
State	Published - Nov 21 2023

Funding

We thank Drs. Samuel D. Rabkin and Jian Hu for providing 005 GSCs and QPP7 GSC, respectively, Dr. Michael A. Curran for the help of developing HIF1α-mKO mice, and Wen-Hao Hsu for the help with single-cell sequencing data analysis. This work was supported in part by NIH R00 CA240896 (P.C.), NIH R01 NS124594 (P.C.), NIH R01 NS127824 (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.), and the Northwestern Medicine Malnati Brain Tumor Insitute of the Robert H. Lurie Comprehensive Cancer Center (P.C.). Imaging and flow cytometry work was performed at the Northwestern University Center for Advanced Microscopy and Flow Cytometry Core Facility supported by NCI CCSG P30 CA060553 . IncuCyte analysis was performed in the Analytical bioNanoTechnology Core (ANTEC) Facility supported by the Soft and Hybrid Nanotechnology Experimental (SHyNE) Resource (NSF ECCS-2025633 ).

Keywords

LGMN
glioblastoma
hypoxia
immunosuppression
immunotherapy
macrophages
protease

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.xcrm.2023.101238

Cite this

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title = "Hypoxia-driven protease legumain promotes immunosuppression in glioblastoma",

abstract = "Glioblastoma (GBM) is a hypoxic and “immune-cold” tumor containing rich stromal signaling molecules and cell populations, such as proteases and immunosuppressive tumor-associated macrophages (TAMs). Here, we seek to profile and characterize the potential proteases that may contribute to GBM immunosuppression. Legumain (LGMN) emerges as the key protease that is highly enriched in TAMs and transcriptionally upregulated by hypoxia-inducible factor 1-alpha (HIF1α). Functionally, the increased LGMN promotes TAM immunosuppressive polarization via activating the GSK-3β-STAT3 signaling pathway. Inhibition of macrophage HIF1α and LGMN reduces TAM immunosuppressive polarization, impairs tumor progression, enhances CD8+ T cell-mediated anti-tumor immunity, and synergizes with anti-PD1 therapy in GBM mouse models. Thus, LGMN is a key molecular switch connecting two GBM hallmarks of hypoxia and immunosuppression, providing an actionable therapeutic intervention for this deadly disease.",

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author = "Lizhi Pang and Songlin Guo and Fatima Khan and Madeline Dunterman and Heba Ali and Yang Liu and Yuyun Huang and Peiwen Chen",

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doi = "10.1016/j.xcrm.2023.101238",

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AU - Pang, Lizhi

AU - Guo, Songlin

AU - Khan, Fatima

AU - Dunterman, Madeline

AU - Ali, Heba

AU - Liu, Yang

AU - Huang, Yuyun

AU - Chen, Peiwen

PY - 2023/11/21

Y1 - 2023/11/21

N2 - Glioblastoma (GBM) is a hypoxic and “immune-cold” tumor containing rich stromal signaling molecules and cell populations, such as proteases and immunosuppressive tumor-associated macrophages (TAMs). Here, we seek to profile and characterize the potential proteases that may contribute to GBM immunosuppression. Legumain (LGMN) emerges as the key protease that is highly enriched in TAMs and transcriptionally upregulated by hypoxia-inducible factor 1-alpha (HIF1α). Functionally, the increased LGMN promotes TAM immunosuppressive polarization via activating the GSK-3β-STAT3 signaling pathway. Inhibition of macrophage HIF1α and LGMN reduces TAM immunosuppressive polarization, impairs tumor progression, enhances CD8+ T cell-mediated anti-tumor immunity, and synergizes with anti-PD1 therapy in GBM mouse models. Thus, LGMN is a key molecular switch connecting two GBM hallmarks of hypoxia and immunosuppression, providing an actionable therapeutic intervention for this deadly disease.

AB - Glioblastoma (GBM) is a hypoxic and “immune-cold” tumor containing rich stromal signaling molecules and cell populations, such as proteases and immunosuppressive tumor-associated macrophages (TAMs). Here, we seek to profile and characterize the potential proteases that may contribute to GBM immunosuppression. Legumain (LGMN) emerges as the key protease that is highly enriched in TAMs and transcriptionally upregulated by hypoxia-inducible factor 1-alpha (HIF1α). Functionally, the increased LGMN promotes TAM immunosuppressive polarization via activating the GSK-3β-STAT3 signaling pathway. Inhibition of macrophage HIF1α and LGMN reduces TAM immunosuppressive polarization, impairs tumor progression, enhances CD8+ T cell-mediated anti-tumor immunity, and synergizes with anti-PD1 therapy in GBM mouse models. Thus, LGMN is a key molecular switch connecting two GBM hallmarks of hypoxia and immunosuppression, providing an actionable therapeutic intervention for this deadly disease.

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Hypoxia-driven protease legumain promotes immunosuppression in glioblastoma

Abstract

Funding

Keywords

ASJC Scopus subject areas

UN SDGs

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