Prospective Molecular Profiling of Circulating Tumor Cells from Patients with Melanoma Receiving Combinatorial Immunotherapy
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE100565 | GEO | 2018/06/26
REPOSITORIES: GEO
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Project description:BACKGROUND:Blood molecular profiling of circulating tumor cells (CTCs) can enable monitoring of patients with metastatic melanoma during checkpoint inhibitor immunotherapy (CII) and in combination with targeted therapies. We developed a microfluidics-based CTC platform to explore CTC profiling utility in CII-treated patients with melanoma using a melanoma messenger RNA (mRNA)/DNA biomarker panel. METHODS:Blood samples (n = 213) were collected prospectively from 75 American Joint Committee on Cancer-staged III/IV melanoma patients during CII treatment and those enriched for CTCs. CTC profiling was performed using 5 known melanoma mRNA biomarkers and BRAF V600E DNA mutation. CTC biomarker status associations with clinical outcomes were assessed. RESULTS:CTCs were detected in 88% of blood samples from patients with melanoma. CTC-derived biomarkers and clinical variables analyzed using classification and regression tree analysis revealed that a combination of lactate dehydrogenase, CTC-mRNA biomarkers, and tumor BRAF-mutation status was indicative of clinical outcomes for patients with stage IV melanoma (n = 52). The panel stratified low-risk and high-risk patients, whereby the latter had poor disease-free (P = 0.03) and overall survival (P = 0.02). Incorporation of a DNA biomarker with mRNA profiling increased overall CTC-detection capability by 57% compared to mRNA profiling only. RNA sequencing of isolated CTCs identified significant catenin beta 1 (CTNNB1) overexpression (P <0.01) compared to nondisease donor blood. CTC-CTNNB1 was associated with progressive disease/stable disease compared to complete-responder patient status (P = 0.02). Serial CTC profiling identified subclinical disease in patients who developed progressive disease during treatment/follow-up. CONCLUSIONS:CTC-derived mRNA/DNA biomarkers have utility for monitoring CII, targeted, and combinatorial therapies in metastatic melanoma patients.
| S-EPMC7193771 | biostudies-literature
Project description:Melanoma is an invasive malignancy with a high frequency of blood-borne metastases, but circulating tumor cells (CTCs) have not been readily isolated. We adapted microfluidic CTC capture to a tamoxifen-driven B-RAF/PTEN mouse melanoma model. CTCs were detected in all tumor-bearing mice, rapidly declining after B-RAF inhibitor treatment. CTCs were shed early from localized tumors and a short course of B-RAF inhibition following surgical resection was sufficient to dramatically suppress distant metastases. The large number of CTCs in melanoma-bearing mice enabled comparison of RNA sequencing profiles with the matched primary tumor. A mouse melanoma CTC-derived signature correlated with invasiveness and cellular motility in human melanoma. In patients with metastatic melanoma, CTCs were detected in smaller numbers in patients with metastatic melanoma and declined with successful B-RAF targeted therapy. Together, the capture of CTCs and their molecular characterization provide insight into the hematogenous spread of melanoma.
2014-03-31 | GSE52031 | GEO
Project description:Melanoma is an invasive malignancy with a high frequency of blood-borne metastases, but circulating tumor cells (CTCs) have not been readily isolated. We adapted microfluidic CTC capture to a tamoxifen-driven B-RAF/PTEN mouse melanoma model. CTCs were detected in all tumor-bearing mice, rapidly declining after B-RAF inhibitor treatment. CTCs were shed early from localized tumors and a short course of B-RAF inhibition following surgical resection was sufficient to dramatically suppress distant metastases. The large number of CTCs in melanoma-bearing mice enabled comparison of RNA sequencing profiles with the matched primary tumor. A mouse melanoma CTC-derived signature correlated with invasiveness and cellular motility in human melanoma. In patients with metastatic melanoma, CTCs were detected in smaller numbers in patients with metastatic melanoma and declined with successful B-RAF targeted therapy. Together, the capture of CTCs and their molecular characterization provide insight into the hematogenous spread of melanoma. We adapted a microfluidic platform, the HbCTC-Chip (Stott et al., 2010, Pubmed ID: 20930119), to capture melanoma CTCs derived from mouse tumors, using panels of antibodies against melanoma-specific cell surface markers, followed by staining for melanoma antigens and optimized on-chip fluorescent imaging. We used a tamoxifen inducible BRAF(CA/+)/PTEN(flox/flox) melanoma mouse model (Dankort et al., 2009, Pubmed ID: 19282848) derived from a C57BL/6 background. Such mice received focal subcutaneous injection of tamoxifen (Sigma) (50ul at 5mg/ml in 50% EtOH suspension) at the left flank at 6-7 weeks after birth. Blood samples were collected from five mice with high tumor burden following tamoxifen injection. Blood from each mouse was split and processed through the CTC-chips functionalized with anti-CSPG4/MCAM antibody and control IgGs, respectively. Matched primary (from the tamoxifen injection site) and metastatic (from upper or lower back) tumors were harvested from the same mouse and immediately flash-frozen in liquid nitrogen. RNA extraction, single molecular sequencing and determination of Digital Gene Expression was as in Yu et al., 2012 (Pubmed ID: 22763454). One of the five mice yielded no CTC or IgG data. In addition, skin was taken from a sixth mouse, which was a complete wild type C57BL/6 mouse (without the BRAF/PTEN transgenes).The skin was taken after euthanasia of the animal and was processed as the tissue from the matched primary and metastatic tumors.
2014-03-31 | E-GEOD-52031 | biostudies-arrayexpress
Project description:Immunotherapy has revolutionized cancer treatment, yet most patients do not respond. Here, we investigated mechanisms of response by deeply profiling the proteome of clinical samples from advanced stage melanoma patients undergoing either tumor infiltrating lymphocytes (TIL)-based or anti-PD1 immunotherapy. Using high-resolution mass spectrometry, we quantified over 10,300 proteins with high accuracy. Statistical analyses revealed higher oxidative phosphorylation and lipid metabolism in responders in both treatments, and identified proteomic signatures for response. Aiming to elucidate the effects of the metabolic state on the immune response, we examined melanoma cells upon metabolic perturbations or Crisp-Cas9 knockouts. These experiments indicated lipid metabolism as a regulatory mechanism that increases melanoma immunogenicity by elevating antigen presentation, thereby affecting the sensitivity to T-cell mediated killing both in-vitro and in-vivo. Altogether, our proteomic analyses revealed novel association between the melanoma metabolic state and the response to immunotherapy, which can be the basis for future improvement of therapeutic response.
2019-07-29 | PXD006003 | Pride
Project description:Observational study to allow the collection of blood and medical information to evaluate the role of circulating tumor material in patients with colorectal cancer and melanoma
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Project description:RATIONALE: Immunotherapy uses different ways to stimulate the immune system and stop cancer cells from growing. Immunotherapy biological extracts may be useful as adjuvant therapy in treating patients who have had surgery for breast cancer, colon cancer, or melanoma.
PURPOSE: Phase III trial to study the effectiveness of Corynebacterium granulosum extract as maintenance immunotherapy following surgery in treating patients with breast cancer, colon cancer, or melanoma.
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Project description:Despite the successful application of immunotherapy, both innate and acquired resistance are typical in melanoma. Ferroptosis induction appears to be a potential strategy to enhance the effectiveness of immunotherapy. However, the relationship between the status of ferroptosis and the effectiveness of immunotherapy, as well as viable strategies to augment ferroptosis, remain unclear. In this study, through large-scale drug screening of cardiovascular drugs, we identified propafenone, an anti-arrhythmia medication, as capable of synergizing with ferroptosis inducers in melanoma. Furthermore, we observed that propafenone, in combination with RSL3, collaboratively induces mitochondrial-associated ferroptosis. Mechanistically, propafenone transcriptionally upregulates mitochondrial HMOX1 via activation of the JNK/JUN signaling pathway under RSL3 treatment, leading to overloaded ferrous iron and ROS within the mitochondria. In xenograft models, the combination of propafenone with ferroptosis induction led to nearly complete tumor regression. Consistently, propafenone enhances immunotherapy-induced antitumor immunity and tumoral ferroptosis in tumor-bearing mice. Significantly, patients exhibiting high levels of ferroptosis/JUN/HMOX1 exhibited improved efficacy of immunotherapy and prolonged progression-free survival. These findings suggest that propafenone holds promise as a candidate drug for enhancing the efficacy of immunotherapy and other ferroptosis-targeted therapies in the treatment of melanoma.
2024-10-26 | GSE279924 | GEO
Project description:Immune checkpoint inhibitors are used to restore or augment antitumor immune response and show great promise in treatment of melanoma and other types of cancers. However, only a relatively small percentage of patients are fully responsive to immune checkpoint inhibition, mostly due to tumor heterogeneity and primary resistance to therapy. Both of these features are largely driven by accumulation of patient-specific mutations, pointing to the need for personalized approaches in diagnostics and immunotherapy. Proteogenomics integrates patient-specific genomic and proteomic data to study cancer development and resistance mechanisms, as well as tumor heterogeneity in individual patients. Here, we use a proteogenomic approach to characterize the mutational landscape of samples derived from four clinical melanoma patients at the genomic, proteomic and phosphoproteomic level. Integration of datasets enabled identification and quantification of an extensive number of sample-specific amino acid variants, among them many were not previously reported in melanoma. We detected a disproportional number of alternate peptides between treated and untreated (naïve) samples with a high potential to influence signal transduction. This is one of the first proteogenomic study designed to study the mutational landscape of patient-derived melanoma tissue samples in response to immunotherapy.
2022-02-16 | PXD028700 | Pride
Project description:The current standard for investigating tumors is surgical biopsy, which is costly, invasive, and difficult to perform serially. As an adjunct, circulating tumor cells (CTCs)—cells that have broken away from the primary tumor or metastatic sites—can be obtained from a blood draw and offer the potential for obtaining serial genetic information and serving as biomarkers. Here, we detail the potential for melanoma CTCs to serve as biomarkers and discuss a clinically viable methodology for single-cell CTC isolation and analysis that overcomes previous limitations. We explore the use of melanoma CTC biomarkers by isolating and performing single-cell RNA sequencing on CTCs from melanoma patients. We then compared transcriptional profiles of single melanoma CTCs against A375 cells and peripheral blood mononuclear cells to identify unique genes differentially regulated in circulating melanoma tumor cells. The information that can be obtained via analysis of these CTCs has significant potential in disease tracking.
2024-02-07 | GSE255299 | GEO
Project description:Immunotherapy efficacy is limited in melanoma, and combinations of immunotherapies with other modalities have yielded limited improvements but also adverse events requiring cessation of treatment. In addition to ineffective patient stratification, efficacy is impaired by paucity of intratumoral immune cells (itICs)—thus, effective strategies to safely increase itICs are needed. We report that dietary administration of L-fucose induces fucosylation and cell surface enrichment of the MHC-II protein HLA-DRB1 in melanoma cells, triggering CD4+T cell-mediated increases in ItICs and anti-tumor immunity, enhancing immune checkpoint blockade responses. Melanoma fucosylation and fucosylated HLA-DRB1 associate with intratumoral T cell abundance and anti-PD1 responder status in patient melanoma specimens, suggesting the potential use of melanoma fucosylation as a strategy for stratifying patients for immunotherapies. Our findings demonstrate that fucosylation is a key mediator of anti-tumor immunity, and importantly, suggest that L-fucose is a powerful agent for safely increasing ItICs and immunotherapy efficacy in melanoma.
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