Data from GLI2 Facilitates Tumor Immune Evasion and Immunotherapeutic Resistance by Coordinating WNT and Prostaglandin Signaling

• DOI: 10.1158/0008-5472.c.7798982
• Publication Date: 2025-05-02T07:23:35Z
• Authors: Nicholas C. DeVito; Y-Van Nguyen; Michael Sturdivant; Michael P. Plebanek; Kaylee A. Villarreal; Nagendra Yarla; Vaibhav Jain; Michael Aksu; Georgia M. Beasley; Balamayooran Thei...; Brent A. Hanks
• Keywords: Evasion (ethics)

<div>Abstract<p>Therapeutic resistance to immune checkpoint blockade has been commonly linked the process of mesenchymal transformation (MT) and remains a prevalent obstacle across many cancer types. An improved mechanistic understanding for MT-mediated evasion promises lead more effective combination therapeutic regimens. Herein, we identified hedgehog transcription factor, GLI2, as key node tumor-mediated immunotherapy during MT. GLI2 generated an immunotolerant tumor microenvironment through upregulation WNT ligand production increased prostaglandin synthesis. This pathway drove recruitment, viability, function granulocytic myeloid-derived suppressor cells while also impairing type I conventional dendritic cell, CD8<sup>+</sup> T-cell, NK cell functionality. Pharmacologic inhibition EP2/EP4 receptor signaling or secretion each reversed subset immunomodulatory effects prevented primary adaptive anti–PD-1 immunotherapy, respectively. A transcriptional signature correlated with in patients stage IV melanoma. Together, these findings provide translational roadmap direct immunotherapies clinic.</p><p><b>Significance:</b> generate environment GLI2-active tumors can be targeted component immunotherapeutic strategies overcome exhibiting plasticity.</p></div>