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Gli2 Facilitates Tumor Immune Evasion and Immunotherapeutic Resistance by Coordinating Wnt Ligand and Prostaglandin Signaling.

Publication ,  Journal Article
DeVito, NC; Nguyen, Y-V; Sturdivant, M; Plebanek, MP; Howell, K; Yarla, N; Jain, V; Aksu, M; Beasley, G; Theivanthiran, B; Hanks, BA
Published in: bioRxiv
April 1, 2024

UNLABELLED: Therapeutic resistance to immune checkpoint blockade has been commonly linked to the process of mesenchymal transformation (MT) and remains a prevalent obstacle across many cancer types. An improved mechanistic understanding for MT-mediated immune evasion promises to lead to more effective combination therapeutic regimens. Herein, we identify the Hedgehog transcription factor, Gli2, as a key node of tumor-mediated immune evasion and immunotherapy resistance during MT. Mechanistic studies reveal that Gli2 generates an immunotolerant tumor microenvironment through the upregulation of Wnt ligand production and increased prostaglandin synthesis. This pathway drives the recruitment, viability, and function of granulocytic myeloid-derived suppressor cells (PMN-MDSCs) while also impairing type I conventional dendritic cell, CD8 + T cell, and NK cell functionality. Pharmacologic EP2/EP4 prostaglandin receptor inhibition and Wnt ligand inhibition each reverses a subset of these effects, while preventing primary and adaptive resistance to anti-PD-1 immunotherapy, respectively. A transcriptional Gli2 signature correlates with resistance to anti-PD-1 immunotherapy in stage IV melanoma patients, providing a translational roadmap to direct combination immunotherapeutics in the clinic. SIGNIFICANCE: Gli2-induced EMT promotes immune evasion and immunotherapeutic resistance via coordinated prostaglandin and Wnt signaling.

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Published In

bioRxiv

DOI

EISSN

2692-8205

Publication Date

April 1, 2024

Location

United States
 

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DeVito, N. C., Nguyen, Y.-V., Sturdivant, M., Plebanek, M. P., Howell, K., Yarla, N., … Hanks, B. A. (2024). Gli2 Facilitates Tumor Immune Evasion and Immunotherapeutic Resistance by Coordinating Wnt Ligand and Prostaglandin Signaling. BioRxiv. https://doi.org/10.1101/2024.03.31.587500
DeVito, Nicholas C., Y-Van Nguyen, Michael Sturdivant, Michael P. Plebanek, Kaylee Howell, Nagendra Yarla, Vaibhav Jain, et al. “Gli2 Facilitates Tumor Immune Evasion and Immunotherapeutic Resistance by Coordinating Wnt Ligand and Prostaglandin Signaling.BioRxiv, April 1, 2024. https://doi.org/10.1101/2024.03.31.587500.
DeVito NC, Nguyen Y-V, Sturdivant M, Plebanek MP, Howell K, Yarla N, et al. Gli2 Facilitates Tumor Immune Evasion and Immunotherapeutic Resistance by Coordinating Wnt Ligand and Prostaglandin Signaling. bioRxiv. 2024 Apr 1;
DeVito, Nicholas C., et al. “Gli2 Facilitates Tumor Immune Evasion and Immunotherapeutic Resistance by Coordinating Wnt Ligand and Prostaglandin Signaling.BioRxiv, Apr. 2024. Pubmed, doi:10.1101/2024.03.31.587500.
DeVito NC, Nguyen Y-V, Sturdivant M, Plebanek MP, Howell K, Yarla N, Jain V, Aksu M, Beasley G, Theivanthiran B, Hanks BA. Gli2 Facilitates Tumor Immune Evasion and Immunotherapeutic Resistance by Coordinating Wnt Ligand and Prostaglandin Signaling. bioRxiv. 2024 Apr 1;

Published In

bioRxiv

DOI

EISSN

2692-8205

Publication Date

April 1, 2024

Location

United States