Gli2 Facilitates Tumor Immune Evasion and Immunotherapeutic Resistance by Coordinating Wnt Ligand and Prostaglandin Synthesis [scRNAseq]

Therapeutic resistance to immune checkpoint blockade remains a prevalent obstacle across many cancer types, and an improved mechanistic understanding of this process could lead to effective combination treatments. Herein, we identify the Hedgehog transcription factor Gli2 as a key node of tumor-mediated immune evasion during mesenchymal transition via the production of Wnt ligands and prostaglandins. This promotes an immune microenvironment rich in PMN-MDSCs, while lacking antigen-presenting cDC1s and effector cells. Gli2-active tumors resist anti-PD-1 treatment, this can be overcome with inhibition of Wnt ligand secretion and selective prostaglandin receptor blockade. The identification of a Gli2 signature in patient samples provides a translational roadmap to direct precision combination immunotherapeutics in the clinic. C57Bl6 mice with control (NTC) or Gli2 active (Gli2CA) BRAF V600E PTEN -/- tumors treated for ~14 days with IgG control; Gli2CA tumors treated with TPST-1495 (selective prostaglandin receptor antagonist) or ETC-159 (PORCN inhibitor)