Defining T Cell States Associated with Response to Checkpoint Immunotherapy in Melanoma
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PROVIDER: PRJNA489547 | ENA |
REPOSITORIES: ENA
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Project description:Defining T Cell States Associated with Response to Checkpoint Immunotherapy in Melanoma
| PRJNA489548 | ENA
Project description:Defining T cell states associated with response to checkpoint immunotherapy in melanoma
| PRJNA493623 | ENA
Project description:we profiled 16,291 immune cells from 48 tumor samples of melanoma patients treated with checkpoint inhibitors, using single-cell transcriptomics.
2018-10-05 | GSE120575 | GEO
Project description:Treatment of cancer has been revolutionized by immune checkpoint blockade therapies. Despite the high rate of response in advanced melanoma, the majority of patients succumb to disease. To identify factors associated with success or failure of checkpoint therapy, we profiled transcriptomes of 16,291 individual immune cells from 48 tumor samples of melanoma patients treated with checkpoint inhibitors. Two distinct states of CD8+ T cells were defined by clustering and associated with patient tumor regression or progression. A single transcription factor, TCF7, was visualized within CD8+ T cells in fixed tumor samples and predicted positive clinical outcome in an independent cohort of checkpoint-treated patients. We delineated the epigenetic landscape and clonality of these T cell states and demonstrated enhanced antitumor immunity by targeting novel combinations of factors in exhausted cells. Our study of immune cell transcriptomes from tumors demonstrates a strategy for identifying predictors, mechanisms, and targets for enhancing checkpoint immunotherapy.
| S-EPMC6641984 | biostudies-literature
Project description:Predicting the outcome of immunotherapy treatment in melanoma patients is challenging. Alterations in genes involved in antigen presentation and the interferon gamma (IFN) pathway play an important role in the immune response to tumors. We describe here that the overexpression of PSMB8 and PSMB9, two components of the immunoproteasome, is predictive of better survival and improved response to immune-checkpoint inhibitors of melanoma patients. We study the mechanism that underlies this connection by analyzing the antigenic peptide repertoire of cells that overexpress these subunits using HLA peptidomics. We find a higher response of patient-matched tumor infiltrating lymphocytes against antigens deferentially presented after immunoproteasome overexpression. which may explain the higher immune infiltration observed in patients with high immunoproteasome expression levels. Importantly, we find that PSMB8 and PSMB9 expression levels are much stronger predictors of melanoma patients immune response to checkpoint inhibitors than the tumors mutational burden. Taken together, these results suggest that their expression levels can serve as important biomarkers for stratifying melanoma patients for immune-checkpoint treatment.
2020-02-18 | PXD015957 | Pride
Project description:<p>Checkpoint blockade therapy using antibodies targeting CTLA4, PD1 or PDL1 have changed the way cancer patients with advanced disease are being treated, as evident by their FDA approval in a wide variety of malignancies, and their ability to induce high response rates when compared to conventional therapies (e.g. chemotherapy). However, even in melanoma, despite the high response rate, most patients are refractory to therapy or acquire resistance in 10-12 months. To identify key immunological elements coupled with response or resistance to checkpoint immunotherapy, we performed an unbiased analysis on 16,291 CD45+ immune cells from 32 patients (48 samples) treated with checkpoint therapy (anti-PD1=37; anti-PD1/CTLA4=11), using single cell transcriptomics. Initial unsupervised clustering of all CD45+ cells identified 11 clusters. When examining the association of these clusters with clinical outcome, we found that two clusters (B-cells, p=0.005; memory T-cells, p=0.03) were significantly enriched in responder lesions while 4 clusters (monocytes/macrophages, p=0.003; dendritic cells, p=0.015; exhausted CD8+ T-cells, p=0.005; and exhausted/cell-cycle lymphocytes, 1.3x10<sup>-5</sup>) are enriched in non-responder lesions. Next, by leveraging our unbiased single cell approach, we identified not only clusters but also specific markers associated with either responder lesions (PLAC8, LTB, LY9, SELL, TCF7, IGKC and CCR7) or non-responder ones (CCL3, CD38, HAVCR2, ENTPD1 and WARS), many of which were not previously reported to be associated with clinical outcome to checkpoint therapy. Due to the importance of CD8+ T-cells in controlling tumors, the significant association of T-cell states with clinical outcome, and their high abundance in melanoma tumors, we next focused our analysis on CD8+ T-cells and identified 2 main clusters CD8_G (with increased expression of genes linked to memory) and CD8_B (enriched for genes linked to cell dysfunction), that were significantly enriched in responder (CD8_G, p=1.4x10<sup>-6</sup>) and non-responder (CD8_B, p=0.005) lesions, respectively. Since cells with both states coexist in each of the responder and non-responder lesions, we decided to calculate the ratio between the number of cells in these 2 clusters and observed a significant separation between responders (CD8_G/CD8_B>1) and non-responders (CD8_G/CD8_B<1) when looking at all samples, baseline or post samples separately. Similar results were detected when looking at the expression of a single transcription factor, TCF7, in CD8 T-cells in an independent cohort (n=43) using a simple immunofluorescence assay. Additionally, we validated the identity and function of some of the newly identified cell states as well as their epigenetic landscape, and found that cells expressing the inhibitory molecules CD39 and TIM3, on top of being enriched in non-responder lesions, are likely to play a crucial role in T-cell exhaustion in melanoma. Collectively, our study provides extensive unbiased data in human tumors for discovery of predictors and therapeutic targets to checkpoint immunotherapy.</p>
| phs001680 | dbGaP
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:We evaluated the editome of melanoma cell lines generated from patients pre- and post-immunotherapy with immune checkpoint inhibitors by RNAseq. Our results reveal a differential editing in Alu sequences between samples pre-therapy and relapses during therapy with immune checkpoint inhibitors
2020-11-25 | GSE162095 | GEO
Project description:Biomarkers of response and resistance to checkpoint blockade immunotherapy in metastatic melanoma
| PRJEB23709 | ENA
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