High response rate to anti PD-1 therapy in desmoplastic melanoma
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PROVIDER: PRJNA414014 | ENA |
REPOSITORIES: ENA
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Project description:High response rate to anti PD-1 therapy in desmoplastic melanoma
| PRJNA414013 | ENA
Project description:<p>Desmoplastic melanoma (DM) is a rare subtype of melanoma characterized by dense fibrous stroma, resistance to chemotherapy and a lack of actionable driver mutations, but is highly associated with ultraviolet light DNA damage. We analysed 60 patients with advanced DM treated with programmed cell death 1 (PD-1) or PD-1 ligand (PD-L1) blocking antibody therapy. Objective tumor responses were observed in 42 of the 60 patients (70%, 95% confidence interval 57-81%), including 19 patients (32% overall) with a complete response. Whole-exome sequencing revealed a high mutational load and frequent NF-1 mutations (14 out of 17 cases). Immunohistochemistry (IHC) analysis from 19 DM and 13 non-DM revealed a higher percentage of PD-L1 positive cells in the tumor parenchyma in DM (p = 0.04), highly associated with increased CD8 density and PD-L1 expression in the tumor invasive margin. Therefore, patients with advanced DM derive significant clinical benefit from PD-1/PD-L1 immune checkpoint blockade therapy despite being a cancer defined by its dense desmoplastic fibrous stroma. The benefit is likely derived from the high mutational burden and a frequent pre-existing adaptive immune response limited by PD-L1 expression.</p>
| phs001469 | dbGaP
Project description:High resolution aCGH was performed on 10 primary Desmoplastic Melanomas (DMs). DMs are a rare subtype of melanoma known for their pronounced desmoplastic stroma and spindled melanocytes. 10 samples were hybridized to Agilent 1 Million feature two color arrays as compared to a panel of normal male DNA. 6 samples were hybridized to Agilent 244K feature two color arrays as compared to a panel of normal male DNA. 34 samples were hybridized to Agilent 180K feature two color arrays as compared to a panel of normal male DNA. 50 unique primary tumors were hybridized compared to normal male DNA.
2015-08-07 | E-GEOD-55150 | biostudies-arrayexpress
Project description:High resolution aCGH was performed on 10 primary Desmoplastic Melanomas (DMs). DMs are a rare subtype of melanoma known for their pronounced desmoplastic stroma and spindled melanocytes. 10 samples were hybridized to Agilent 1 Million feature two color arrays as compared to a panel of normal male DNA. 6 samples were hybridized to Agilent 244K feature two color arrays as compared to a panel of normal male DNA. 34 samples were hybridized to Agilent 180K feature two color arrays as compared to a panel of normal male DNA.
2015-08-07 | GSE55150 | GEO
Project description:Genetic analysis of desmoplastic melanoma
| PRJNA293389 | ENA
Project description:Background: Inducible nitric oxide synthase (iNOS) and its product nitric oxide (NO) were historically linked to poor melanoma outcomes, yet recent evidence shows NO supports anti-tumor immunity. This study examines how iNOS shapes anti–PD-1 efficacy, particularly through interferon signaling. Methods: B16 D5 melanoma tumors were implanted in wild-type (WT) and iNOS knockout (KO) mice to compare tumor growth and response to anti–PD-1 therapy. Flow cytometry, apoptosis assays, and RNA sequencing assessed NO production, PD-L1 expression, and interferon-related gene activation. In vitro, melanoma cells were treated with NO donors (DETA NONOate, SNAP) to assess proliferation and apoptosis. Peripheral blood mononuclear cells from 27 melanoma patients receiving anti–PD-1 therapy were analyzed with multiparameter flow cytometry to correlate NO-associated immune subsets with progression-free survival (PFS). Results: Tumors grew significantly faster in iNOS KO mice, and anti–PD-1 therapy had no effect, demonstrating that iNOS-derived NO contributes to treatment efficacy. NO donors inhibited melanoma proliferation and induced apoptosis in vitro. Transcriptomic analysis showed anti–PD 1 upregulated interferon pathway genes (STAT1, IRF1, IFNB1) in WT but not iNOS KO mice. In patients, a NO-producing dendritic cell subset (DAF FM⁺CD11c⁺) was associated with improved PFS (hazard ratio 0.453; 95% CI=0.270-0.992; p = 0.048), indicating a NO-dependent enhancement of interferon-driven immune activity.
2026-07-15 | GSE334585 | GEO
Project description:KIT is a key oncogenic driver in triple-wildtype melanoma and represents a rational therapeutic target for KIT inhibitors such as imatinib. However, the tumor immune microenvironment in KIT-altered melanoma and optimal strategies to integrate immunotherapy remain poorly defined. In this study, we found that melanomas harboring KIT mutations or amplifications exhibited reduced CD8⁺ T cell infiltration, indicative of an immune-cold phenotype. Imatinib treatment reversed this Immunosuppressive microenvironment by enhancing CD8⁺ T cell infiltration and cytotoxic activity. Furthermore, imatinib upregulated O-GlcNAc transferase (OGT), which functions as a protein lactyltransferase and increased PD-L1 expression through lysine lactylation, thereby sensitizing tumors to anti–PD-1 therapy. Based on these findings, we conducted an open-label, single-arm phase II clinical trial in patients with advanced or metastatic KIT-altered melanoma. Patients received imatinib monotherapy as induction for six weeks, followed by combination therapy with toripalimab, an anti–PD-1 antibody. The combiniation therapy was well-tolerated and demonstrated encouraging clinical activity, with an objective response rate (ORR) of 59.4% in the overall cohort, 73.9% in patients with exon 11/13 mutations, and 100% in those with exon 11 mutation plus amplification—markedly higher than the ORRs of 23.3% with imatinib monotherapy and 25.7% with anti–PD-1 monotherapy. Median progression-free survival and overall survival were 8.2 months (95% CI, 6.5–9.9) and 15.1 months (95% CI, 13.1–20.8), respectively. These results support the use of imatinib as an immune-sensitizing induction therapy prior to PD-1 blockade in KIT-altered melanoma and highlight the therapeutic relevance of OGT-mediated PD-L1 regulation.
2026-07-23 | GSE303456 | GEO
Project description:B cells potentially play a role in the immune response to melanoma, including during treatment with immune modulators. We profiled (transcriptome analysis) effects of anti-PD-L1 antibody therapy on gene expression in B16 melanoma tumors of B cells depleted and WT syngeneic mice. After 7 days of B16 tumors implantation, mice were treated or untreated with anti-PD-L1 antibody (every three days).
2022-05-15 | GSE202879 | GEO
Project description:Blocking the PD-1/PD-L1 immunosuppressive pathway has shown promise in the treatment of certain cancers including melanoma. This study investigates differences in the gene expression profiles of human melanomas that do or do not display the immunosuppressive protein PD-L1. Further understanding of genes expressed within the tumor microenvironment of PD-L1+ tumors may lead to improved rationally designed treatments. Gene expression profiling was performed on total RNA extracted by laser capture microdissection from 11 archived formalin-fixed paraffin-embedded (FFPE) melanoma specimens, 5 of which were PD-L1 positive and 6 PD-L1 negative. Details of the design, and the gene signatures found are given in the paper associated with this GEO Series: Janis M. Taube, Geoffrey D. Young, Tracee L. McMiller, Shuming Chen, January T. Salas, Theresa S. Pritchard, Haiying Xu, Alan K. Meeker, Jinshui Fan, Chris Cheadle, Alan E. Berger, Drew M. Pardoll, and Suzanne L. Topalian, Differential expression of immune-regulatory genes associated with PD-L1 display in melanoma: implications for PD-1 pathway blockade, Clin Cancer Res 2015, in press.
2015-05-01 | E-GEOD-65041 | biostudies-arrayexpress
Project description:Despite high clinical need, hardly any biomarker can accurately predict if patients with metastatic melanoma will respond to anti-PD-1 therapy. In this multicenter study we applied depletion and enrichment methods prior to different proteomic techniques to analyze the discovery cohort (n=56) and discovered several significantly regulated proteins as well as commonly enriched processes such as neutrophil degranulation, cell-substrate adhesion, and extracellular matrix organization. We then analyzed two independent serum cohorts (n=96; n=17) confirming significant differences between R and NR. In addition, literature-based validation revealed 30 markers overlapping with previously published signatures, and survival analysis revealed that overexpression of 17 markers correlated with lower overall survival in melanoma patients. Primary melanoma tumor cells from NR also exhibit a distinctive immunophenotype characterized by CD29, CD49e, CD91, CD105, CD151, CD157, CD248 and CD280, and the TME could represent a potential target for therapy. Ultimately, this led to a potential marker signature with 8 key markers identified in at least two independent serum cohorts: CFHR3, CRP, LRG1, LYVE1, MMRN1, S100A8, SAA2, and TIMP1.
2023-08-18 | PXD039469 | Pride