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Molecular patterns of resistance to immune checkpoint blockade in melanoma [bulk RNA-Seq]

ABSTRACT: Molecular patterns of resistance to immune checkpoint blockade in melanoma [bulk RNA-Seq]

PROVIDER: PRJNA1026569 | ENA |

REPOSITORIES: ENA

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Molecular patterns of resistance to immune checkpoint blockade in melanoma

Project description:Molecular patterns of resistance to immune checkpoint blockade in melanoma

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Molecular patterns of resistance to immune checkpoint blockade in melanoma [NanoString GeoMx]

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Molecular patterns of resistance to immune checkpoint blockade in melanoma [NanoString GeoMx]

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Molecular patterns of resistance to immune checkpoint blockade in melanoma [bulk RNA-Seq]

Project description:Immune checkpoint blockade (ICB) has improved outcome for patients with metastatic melanoma but not all benefit from treatment. Several immune- and tumor intrinsic features are associated with clinical response at baseline. However, we need to further understand the molecular changes occurring during development of ICB resistance. Here, we collected biopsies from a cohort of 44 melanoma patients after progression to anti-CTLA4 or anti-PD1 monotherapy. Genetic alterations of antigen presentation and interferon gamma signaling pathways were observed in approximately 25% of ICB resistant cases. Anti-CTLA4 resistant lesions had a sustained immune response, including immune-regulatory features, as suggested by multiplex spatial and TCR clonality analyses. One anti-PD1 resistant lesion harbored a distinct immune cell niche, however, anti-PD1 resistant tumors were generally immune poor with non-expanded TCR clones. Such immune poor microenvironments were associated with melanoma cells having a de-differentiated phenotype lacking expression of MHC-I molecules. In addition, anti-PD1 resistant tumors had reduced fractions of PD1+ CD8+ T cells as compared to ICB naïve metastases. Collectively, these data show the complexity of ICB resistance and highlight differences between anti-CTLA4 and anti-PD1 resistance that may underlie differential clinical outcomes of therapy sequence and combination.

2024-02-06 | GSE244982 | GEO

Melanoma Sequential Immune Checkpoint Blockade Treatment Sequencing Study

Project description:Melanoma Sequential Immune Checkpoint Blockade Treatment Sequencing Study

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Downregulation of KEAP1 in melanoma promotes resistance to immune checkpoint blockade [scRNA-seq]

Project description:Immune checkpoint blockade (ICB) has demonstrated efficacy in patients with melanoma, but many exhibit poor responses. Using single cell RNA sequencing of melanoma patient-derived circulating tumor cells (CTCs) and functional characterization using mouse melanoma models, we show that the KEAP1/NRF2 pathway modulates sensitivity to ICB, independently of tumorigenesis. The NRF2 negative regulator, KEAP1, shows intrinsic variation in expression, leading to tumor heterogeneity and subclonal resistance.

2023-02-24 | GSE218429 | GEO

Downregulation of KEAP1 in melanoma promotes resistance to immune checkpoint blockade [scBisulfite-seq]

2023-02-24 | GSE218423 | GEO

Molecular patterns of resistance to immune checkpoint blockade in melanoma [scRNA-Seq]

2024-02-06 | GSE244983 | GEO

T cell characteristics associated with toxicity to immune checkpoint blockade in patients with melanoma [bulk RNA-seq]

Project description:Severe immune-related adverse events (irAEs) occur in up to 60% of melanoma patients treated with immune checkpoint inhibitors (ICIs). However, it remains unknown whether a common baseline immunological state precedes irAE development. Leveraging CyTOF, single-cell RNA sequencing, bulk RNA sequencing, and T cell receptor sequencing to analyze pretreatment blood from metastatic melanoma patients treated with ICIs, we investigated cellular factors associated with severe irAE development regardless of organ system involvement. Our results demonstrate circulating T cell characteristics associated with ICI-induced toxicity, with implications for improved diagnostics and clinical management.

2022-01-13 | GSE186143 | GEO

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