Provoking the Immunotherapy Efficacy of Renal Medullary Carcinoma [RNA-seq II]
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PROVIDER: PRJNA1005319 | ENA |
REPOSITORIES: ENA
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Project description:Provoking the Immunotherapy Efficacy of Renal Medullary Carcinoma
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Project description:Provoking the Immunotherapy Efficacy of Renal Medullary Carcinoma [RNA-seq I]
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Project description:Renal medullary carcinoma (RMC) predominantly afflicts young individuals of African descent harboring sickle hemoglobinopathies such as sickle cell disease (SCD) or sickle cell anemia (SCA). RMC is refractory to targeted and immune therapy strategies used for other renal cell carcinomas. We have demonstrated that RMC is resistant to immune checkpoint inhibition despite harboring an inflamed tumor immune microenvironment. Hence, novel therapeutic strategies are urgently needed to reverse this resistance. We discovered that CD8+ T cells under SCD condition exhibit altered genomic architecture and ferroptosis, which significantly impairs the anti-tumor immunity of effector T cells. These observations may underscore a fundamental mechanism behind the distinct resistance of RMC resistance to immune checkpoint therapies. By leveraging the use of both mouse SCD model and humanized mice phenotypically representing SCD/SCA, as well as primary CD8+ T cells isolated from patients with SCA, we identified that the SLC7A11 gene is transcriptionally downregulated in the CD8+ T cells of SCA donors via genomic architecture alteration. The reduced expression of SLC7A11 partially accounts for the ferroptosis observed in the CD8+ T cells of SCD disease, via impairing the cystine transportation and synthesis of Glutathione (GSH). Our findings also demonstrated that treatment using a hydrogen sulfide slow-releasing donor restored the expression of SLC7A11, antagonized the ferroptosis of CD8+ T cells under SCD/SDA condition and restored anti-tumor immunity in vivo. Hence, our research findings provide novel mechanistic insights into SCD and RMC and pave the way to develop innovative therapeutic strategies to sensitize RMC to immune therapies.
2025-07-02 | GSE240827 | GEO
Project description:Renal medullary carcinoma (RMC) predominantly afflicts young individuals of African descent harboring sickle hemoglobinopathies such as sickle cell disease (SCD) or sickle cell anemia (SCA). RMC is refractory to targeted and immune therapy strategies used for other renal cell carcinomas. We have demonstrated that RMC is resistant to immune checkpoint inhibition despite harboring an inflamed tumor immune microenvironment. Hence, novel therapeutic strategies are urgently needed to reverse this resistance. We discovered that CD8+ T cells under SCD condition exhibit altered genomic architecture and ferroptosis, which significantly impairs the anti-tumor immunity of effector T cells. These observations may underscore a fundamental mechanism behind the distinct resistance of RMC resistance to immune checkpoint therapies. By leveraging the use of both mouse SCD model and humanized mice phenotypically representing SCD/SCA, as well as primary CD8+ T cells isolated from patients with SCA, we identified that the SLC7A11 gene is transcriptionally downregulated in the CD8+ T cells of SCA donors via genomic architecture alteration. The reduced expression of SLC7A11 partially accounts for the ferroptosis observed in the CD8+ T cells of SCD disease, via impairing the cystine transportation and synthesis of Glutathione (GSH). Our findings also demonstrated that treatment using a hydrogen sulfide slow-releasing donor restored the expression of SLC7A11, antagonized the ferroptosis of CD8+ T cells under SCD/SDA condition and restored anti-tumor immunity in vivo. Hence, our research findings provide novel mechanistic insights into SCD and RMC and pave the way to develop innovative therapeutic strategies to sensitize RMC to immune therapies.
2025-07-02 | GSE231386 | GEO
Project description:This SuperSeries is composed of the SubSeries listed below.
2025-07-02 | GSE240845 | GEO
Project description:Genomics of pediatric renal medullary carcinomas
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Project description:Genomics of pediatric renal medullary carcinomas
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Project description:Renal medullary carcinoma (RMC) is a rare but highly aggressive malignancy that mainly afflicts young individuals of African descent and has few treatment options. Despite the approval of combination immune checkpoint therapy (ICT) for other kidney cancers, its efficacy against RMC remains elusive. We conducted a prospective clinical trial of nivolumab plus ipilimumab in patients with RMC. Enrollment was halted for futility after a prespecified interim analysis revealed that all 10 patients experienced rapid disease progression with 5/10 meeting radiological criteria for hyperprogression. Median progression-free survival was only 1.38 months (95% confidence interval (CI): 1.28, 1.60). To elucidate the underlying mechanisms, we analyzed high-quality single-cell RNA sequencing data from RMC patients before and after nivolumab plus ipilimumab treatment. Our analysis suggested that ICT-triggered interferon gamma upregulation induces RMC tumor cells to activate key myeloid regulators such as the CEBPB / p300 complex that promote tumor cell proliferation leading to hyperprogression. Using an immunocompetent somatic mosaic genetically engineered mouse model of RMC, we confirmed that combination ICT induced hyperprogression of primary and metastatic tumors compared with IgG control by hijacking myeloid-affiliated transcriptional circuits. Blocking of this “myeloid mimicry” adaptive mechanism using a selective inhibitor of p300 induced sensitivity to combination ICT in our animal model of RMC. These findings provide novel insights into RMC adaptation to ICT and demonstrate that inhibiting master myeloid regulators can elicit antitumor responses to ICT thus informing the next generation of immunotherapy strategies targeting hyperprogression.
2025-06-30 | GSE256326 | GEO
Project description:Tumor microenvironmental cellular components like bone marrow cells stromal cells macrophages changes due to sunitinib resistance may affect their efficacy in advanced stage renal cell carcinomas. Immune checkpoint inhibitors (ICIs) have been approved as 2nd line therapy over acquired resistance. Each ICI uniquely affected different cellular components. Better understanding of transcriptomic, metabolomic or proteomic changes due to ICI treatment is necessary to development proper immunotherapy.
2024-03-07 | GSE226967 | GEO
Project description:Renal medullary carcinomas (RMC) habor a distinct methylation phenotype
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