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

Abstract

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 identified the Hedgehog transcription factor, GLI2, as a key node of tumor-mediated immune evasion and immunotherapy resistance during MT. GLI2 generated an immunotolerant tumor microenvironment through the upregulation of WNT ligand production and increased prostaglandin synthesis. This pathway drove the recruitment, viability, and function of granulocytic myeloid-derived suppressor cells while also impairing type I conventional dendritic cell, CD8+ T cell, and natural killer cell functionality. Pharmacologic inhibition of EP2/EP4 prostaglandin receptor signaling or WNT ligand secretion each reversed a subset of the immunomodulatory effects of GLI2 and prevented primary and adaptive resistance to anti-PD-1 immunotherapy, respectively. A transcriptional GLI2 signature correlated with resistance to anti-PD-1 immunotherapy in stage IV melanoma patients. Together, these findings provide a translational roadmap to direct combination immunotherapies in the clinic.