Gene expression profiles of melanoma tumor samples from patients treated with checkpoint inhibitors (human)
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ABSTRACT:
PROVIDER: PRJNA504015 | ENA |
REPOSITORIES: ENA
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Project description:Tumor samples were obtained from patients with metastatic melanoma before treatment with checkpoint inhibitors.
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Project description:Checkpoint inhibitors have improved outcomes for patients with metastatic melanoma, but primary or acquired resistance often occurs. We used the mouse melanoma cell line B16, originally derived from C57BL6 mice, to model changes in tumor cell gene expression that occur with acquired resistance to checkpoint inhibitors. B16 cells used were engineered to express the fluorescent marker tdTomato, to assist monitoring and cell sorting. Previously-untreated B16 cells (F0) were inoculated into C57BL6 mice, followed by treatment with triple-checkpoint inhibitor therapy (3I) with combined antibodies to CTLA4, PD-1, and PD-L1. Tumors that emerged despite immune selection pressure were harvested, grown again in vitro as a cell line, and then re-inoculated into a new generation of mice. This was repeated for 4 generations (F4) until inoculations were 100% successful at generating immune-resistant tumors.
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Project description:Gene expression profiles of melanoma tumor samples from patients treated with checkpoint inhibitors
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Project description:Gene expression profiles of melanoma tumor samples from patients treated with checkpoint inhibitors (mouse)
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Project description:Recent development of new therapies with immune checkpoint inhibitors (ICIs) and MAPK-inhibitors (MAPKis) have significantly improved the outcome in metastatic cutaneous melanoma (CM). However, therapy response is limited to subgroups of patients and clinically useful predictive biomarkers for treatment outcome are lacking. To discover treatment-related systemic changes in plasma and potential biomarkers associated with treatment outcomes, we analysed 45 plasma samples from 24 patients with metastatic (stage IV) CM, using HiRIEF LC-MS/MS, collected before (pre-trm) and during treatment (trm). Of these, 27 samples were taken from 15 metastatic CM patients treated with ICIs (13 pre-trm and 14 trm samples; 12 matched) and 9 patients treated with MAPKis (9 matched). Matched samples were trm and pre-trm samples taken from the same individual before treatment and after the first cycle of treatment (before the second cycle). We have analysed the change in the plasma protein levels during treatment by comparing the plasma levels in the trm samples to the pre-trm samples, to detect treatment-induced alterations in the plasma proteome. We have analysed the patients treated with ICIs separately from the patients treated with MAPKis, to detect treatment-specific changes for both.
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Project description:This is a simple mathematical population model for pembrolizumab-treated advanced melanoma patients, used to predict the response of melanoma patients to immune checkpoint inhibitors.
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Project description:Multiomics analysis of immune-related adverse events in melanoma patients treated with immune checkpoint inhibitors
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Project description:Immune checkpoint inhibitors (ICIs) are a standard-of-care for the treatment of advanced melanoma, but their use is limited by immune-related adverse events (irAEs). Proteomic analysis and multiplex cytokine/chemokine assay from serum at baseline and at irAEs onset in 82 patients indicated aberrant T-cell activity with differential expression of Type I and III immune signatures. This was in line with an increase in the proportions of monocytes and decrease of IL-17A producing CD4+ T-cells in the peripheral blood in single cell RNA sequencing. Multiplex immunohistochemistry on ICI-induced skin rash and inflamed colon showed increase in the proportion of CD4+ T-cells with IL-17A expression. Anti-IL17A antagonistic mAbs were administered in two patients with severe myocarditis, colitis and skin rash with resolution of the irAE. This study demonstrates the potential role of Type III CD4+ T-cells in the irAEs development and provides proof-of-principle evidence to support a clinical trial examining anti-IL17A in their management.
2023-12-01 | GSE227001 | GEO
Project description:Introduction: Advanced cutaneous melanoma is a skin cancer characterized by a poor prognosis and high metastatic potential. During metastatic spread, melanoma cells often undergo dedifferentiation toward an invasive phenotype, resulting in reduced expression of microphthalmia-associated transcription factor (MITF)-dependent melanoma antigens and facilitating immune escape. Tumor Necrosis Factor (TNF) is known to be a key factor in melanoma dedifferentiation. Interestingly, accumulating evidence suggests that TNF may play a role in melanoma progression and resistance to immunotherapies. Additionally, TNF has been identified as a potent regulator of sphingolipid (SL) metabolism, which could contribute to melanoma aggressiveness and the process of melanoma dedifferentiation. Methods: We conducted RNA sequencing and mass spectrometry analyses to investigate TNF-induced dedifferentiation in two melanoma cell lines. In vitro experiments were performed to manipulate sphingolipid metabolism using genetic or pharmacologic alterations in combination with TNF treatment, aiming to elucidate the potential involvement of this metabolism in TNF-induced dedifferentiation. Lastly, to evaluate the clinical significance of our findings, we performed unsupervised analysis of plasma sphingolipid levels in 48 patients receiving treatment with immune checkpoint inhibitors, either alone or in combination with anti-TNF therapy. Results: Herein, we demonstrate that TNF-induced melanoma cell dedifferentiation is associated with a global modulation of sphingolipid metabolism. Specifically, TNF decreases the expression and activity of acid ceramidase (AC), encoded by the ASAH1 gene, while increasing the expression of glucosylceramide synthase (GCS), encoded by the UGCG gene. Remarkably, knockdown of AC alone via RNA interference is enough to induce melanoma cell dedifferentiation. Furthermore, treatment with Eliglustat, a GCS inhibitor, inhibits TNF-induced melanoma cell dedifferentiation. Lastly, analysis of plasma samples from patients treated with immune checkpoint inhibitors, with or without anti-TNF therapy, revealed significant predictive sphingolipids. Notably, the top 8 predictive sphingolipids, including glycosphingolipids, were associated with a poor response to immunotherapy. Discussion: Our study highlights that ceramide metabolism alterations are causally involved in TNF-induced melanoma cell dedifferentiation and suggests that the evolution of specific ceramide metabolites in plasma may be considered as predictive biomarkers of resistance to immunotherapy.
2024-07-24 | GSE270741 | GEO
Project description:Introduction: Advanced cutaneous melanoma is a skin cancer characterized by a poor prognosis and high metastatic potential. During metastatic spread, melanoma cells often undergo dedifferentiation toward an invasive phenotype, resulting in reduced expression of microphthalmia-associated transcription factor (MITF)-dependent melanoma antigens and facilitating immune escape. Tumor Necrosis Factor (TNF) is known to be a key factor in melanoma dedifferentiation. Interestingly, accumulating evidence suggests that TNF may play a role in melanoma progression and resistance to immunotherapies. Additionally, TNF has been identified as a potent regulator of sphingolipid (SL) metabolism, which could contribute to melanoma aggressiveness and the process of melanoma dedifferentiation. Methods: We conducted RNA sequencing and mass spectrometry analyses to investigate TNF-induced dedifferentiation in two melanoma cell lines. In vitro experiments were performed to manipulate sphingolipid metabolism using genetic or pharmacologic alterations in combination with TNF treatment, aiming to elucidate the potential involvement of this metabolism in TNF-induced dedifferentiation. Lastly, to evaluate the clinical significance of our findings, we performed unsupervised analysis of plasma sphingolipid levels in 48 patients receiving treatment with immune checkpoint inhibitors, either alone or in combination with anti-TNF therapy. Results: Herein, we demonstrate that TNF-induced melanoma cell dedifferentiation is associated with a global modulation of sphingolipid metabolism. Specifically, TNF decreases the expression and activity of acid ceramidase (AC), encoded by the ASAH1 gene, while increasing the expression of glucosylceramide synthase (GCS), encoded by the UGCG gene. Remarkably, knockdown of AC alone via RNA interference is enough to induce melanoma cell dedifferentiation. Furthermore, treatment with Eliglustat, a GCS inhibitor, inhibits TNF-induced melanoma cell dedifferentiation. Lastly, analysis of plasma samples from patients treated with immune checkpoint inhibitors, with or without anti-TNF therapy, revealed significant predictive sphingolipids. Notably, the top 8 predictive sphingolipids, including glycosphingolipids, were associated with a poor response to immunotherapy. Discussion: Our study highlights that ceramide metabolism alterations are causally involved in TNF-induced melanoma cell dedifferentiation and suggests that the evolution of specific ceramide metabolites in plasma may be considered as predictive biomarkers of resistance to immunotherapy.
2024-07-24 | GSE270740 | GEO