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• W4308399077 abstract "<h3>Background</h3> Immunotherapy resistance correlates with mesenchymal transformation (MT),^{1, 2} however we are unable to therapeutically target this immune evasive phenotype. We have shown that in anti-PD-1 resistant melanomas, the Hedgehog (Hh) transcription factor Gli2 drives the upregulation of Wnt and prostaglandin synthesis, which promotes the recruitment of granulocytic myeloid-derived suppressor cells (PMN-MDSCs) leading to immune evasion and immunotherapy failure.^{3, 4} Hh activation has been described in immunotherapy resistance ^{5, 6}, however targeting has focused on SMO inhibition, which is limited by noncanonical pathway activation.^{7, 8} Here, we demonstrate the utility of a Gli2 signature to predict anti-PD-1 immunotherapy failure and determine whether selective prostaglandin receptor inhibition (EP2i/EP4i) can overcome this resistance pathway in melanoma. <h3>Methods</h3> Gli2 was constitutively activated (Gli2^CA) in a BRAF^V600EPTEN^-/- melanoma cell line by inducing an N-terminal truncating mutation. Multi-parameter flow cytometry, RNAseq, and scRNAseq were utilized to evaluate the impact of Gli2 activity and therapeutic treatments on the tumor immune microenvironment. Anti-PD-1, EP2i/EP4i, PORCNi (Wnt ligand inhibition), and PMN-MDSC ablation <i>in vivo</i> studies were performed in Gli2^CA and control tumors. Nanostring analysis was performed on clinical melanoma tumor specimens and bioinformatics studies were conducted using the TCGA and Hugo et al databases.² <h3>Results</h3> Gli2^CA tumors display resistance to anti-PD-1, where flow cytometry revealed persistent exclusion of CD103⁺ antigen-presenting DCs, activated T and NK cells, and greater numbers of PMN-MDSCs compared to control tumors. Gli2 upregulates genes involved in prostaglandin synthesis and PGE2 production, which is ablated in Gli2-knockout melanomas. Treatment with EP2i/EP4i suppresses tumor growth, increasing levels of CD8⁺ T cells, NK cells, and cDC1s in Gli2^CA but not in control tumors; and this is further potentiated by anti-PD-1. EP2i/EP4i markedly reduces PMN-MDSCs in Gli2^CA tumors, and anti-Ly6G depletion of PMN-MDSCs had a similar impact on the immune microenvironment. scRNAseq showed enhanced NK cell activity with EP2i/EP4i over PORCNi in Gli2^CA tumors, and while both therapies reduced PMN-MDSC numbers, EP2i/EP4i also diminished suppressive markers. Gli2 and prostaglandin signatures correlate in the melanoma and colorectal TCGA. Importantly, a Gli2 signature predicts for anti-PD-1 resistance in a subset of melanoma patients. <h3>Conclusions</h3> Gli2 drives the development of a tolerogenic tumor microenvironment during MT via Wnt and prostaglandin signaling, leading to anti-PD-1 failure through enhanced PMN-MDSC recruitment and activity. This state can be reversed with EP2i/EP4i in mouse models. These results suggest that a Gli2 signature may predict for EP2i/EP4i sensitivity in a subset of anti-PD-1 resistant melanomas. <h3>References</h3> Bagaev A, <i>et al</i>. Conserved pan-cancer microenvironment subtypes predict response to immunotherapy. <i>Cancer Cell</i>, 2021. Hugo W. <i>et al</i>. Genomic and Transcriptomic Features of Response to Anti-PD-1 Therapy in Metastatic Melanoma. <i>Cell</i> 2016;<b>165</b>(1): 35–44. DeVito NC, <i>et al</i>. Pharmacological Wnt ligand inhibition overcomes key tumor-mediated resistance pathways to anti-PD-1 immunotherapy. <i>Cell Rep</i> 2021;<b>35</b>(5): 109071. DeVito NC, SM, Nguyen Y, Plebanek M, Thievanthiran B, Liu F, Hanks BA. Hedgehog Signaling Drives Epithelial-to-Mesenchymal Transition, Immune Evasion, and Anti-PD-1 Resistance through Coordinated Upregulation of Wnt Ligands and PGE2 Synthesis. <i>Society for Immunotherapy in Cancer Annual Meeting</i>, 2021. D9Angelo SP, <i>et al</i>. Pilot study of bempegaldesleukin in combination with nivolumab in patients with metastatic sarcoma. <i>Nat Commun</i> 2022;<b>13</b>(1): 3477. Jiang J, <i>et al</i>. Pan-cancer analyses reveal that increased Hedgehog activity correlates with tumor immunosuppression and resistance to immune checkpoint inhibitors. <i>Cancer Med</i>, 2022;<b>11</b>(3): 847–863. Pietrobono S, S Gagliardi, and B Stecca. Non-canonical Hedgehog Signaling Pathway in Cancer: Activation of GLI Transcription Factors Beyond Smoothened. <i>Front Genet</i>, 2019;<b>10</b>: 556. De Jesus-Acosta A, <i>et al</i>. Phase 2 study of vismodegib, a hedgehog inhibitor, combined with gemcitabine and nab-paclitaxel in patients with untreated metastatic pancreatic adenocarcinoma. <i>Br J Cancer</i> 2020;<b>122</b>(4): 498–505. <h3>Ethics Approval</h3> All appropriate ethics approvals were obtained. De-identified human data was obtained from publicly available resources (TCGA, Hugo et al databases). All patients from our internal dataset were collected under IRB protocol #Pro00059349, and animal experiments were conducted with IACUC approval #A114-21-05." @default.
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• W4308399077 date "2022-11-01" @default.
• W4308399077 modified "2023-10-18" @default.
• W4308399077 title "513 Overcoming hedgehog mediated anti-PD-1 resistance in melanoma through prostaglandin inhibition" @default.
• W4308399077 doi "https://doi.org/10.1136/jitc-2022-sitc2022.0513" @default.
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