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: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: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
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:Patients with advanced melanoma have shown an improved outlook after receiving anti-PD1 therapy, but the low response rate restricts clinical benefit; therefore, enhancing anti-PD1 therapy efficacy remains a major challenge. Here, our findings show significantly higher abundance of α-KG in healthy controls, anti-PD1-sensitive melanoma-bearing mice, and anti-PD1-sensitive melanoma patients; moreover, supplementation with α-KG enhanced the efficacy of anti-PD1 immunotherapy and increased PD-L1 expression in melanomas via STAT1/3. We also found that supplementation with α-KG significantly increased methylcytosine dioxygenase TET2/3, which led to an increased 5-hydroxymethylcytosine (5-hmC) level in the PD-L1 promoter. As a consequence, STAT1/3 had been recognized and stabilized in PD-L1 promoter to upregulate PD-L1 expression. Importantly, single-cell sequencing of preclinical samples and analysis of clinical data revealed that the TET2/3-STAT1/3-CD274 signaling was associated with sensitivity to anti-PD1 treatment in melanoma. Taken together, we provide a novel insight into α-KG's function in melanoma anti-PD1 treatment and supplement of α-KG is a novel promising strategy to improve the efficacy of anti-PD1 therapy.
2023-03-08 | GSE223110 | GEO
Project description:Melanoma dedifferentiation has been reported as a state of cellular resistance to targeted therapies and immunotherapies as cancer cells revert to a more primitive cellular phenotype. Here we show that, counterintuitively, the biopsies of patient tumors that respond to anti-programmed cell death receptor 1 (PD-1) therapy decreased expression of melanocytic markers and increased neural crest markers, suggesting treatment-induced dedifferentiation. When modeling the effects in vitro, we documented that melanoma cell lines that were originally melanocytic differentiated underwent a process of neural crest dedifferentiation when continuously exposed to interferon gamma (IFNγ), through a global chromatin landscape changes leading to enrichment in specific hyperaccessible chromatin regions. The IFNγ-induced dedifferentiation signature corresponded with improved outcomes in patients with melanoma, challenging the notion that neural crest dedifferentiation is entirely an adverse phenotype.
2021-05-10 | GSE154483 | GEO