Pyroptosis has profound impacts on tumor cell proliferation, invasion, and metastasis and is of great clinical significance for different cancers. However, the role of pyroptosis in the progression and prognosis of muscle invasive bladder cancer (MIBC) remains poorly characterized. Here, we collected multicenter MIBC data and performed integrated analysis to dissect the role of pyroptosis in MIBC and provide an optimized treatment for this disease. Based on transcriptomic data, we developed a novel prognostic model named the pyroptosis-related gene score (PRGScore), which summarizes immunological features, genomic alterations, and clinical characteristics associated with the pyroptosis phenotype. Samples with high PRGScore showed enhancement in CD8+ T cell effector function, antigen processing machinery and immune checkpoint and better response to immunotherapy by programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1) inhibitors, which indicates that PRGScore is a valuable signature in the identification of populations sensitive to immune checkpoint inhibitors. Collectively, our study provides insights into further research targeting pyroptosis and its tumor immune microenvironment (TME) and offers an opportunity to optimize the treatment of MIBC.
Background Vascular invasion with tumor thrombus frequently occurs in advanced renal cell carcinoma (RCC). Thrombectomy is one of the most challenging surgeries with high rate of perioperative morbidity and mortality. However, the mechanisms driving tumor thrombus formation are poorly understood which is required for designing effective therapy for eliminating tumor thrombus. Results We perform single-cell RNA sequencing analysis of 19 surgical tissue specimens from 8 clear cell renal cell carcinoma (ccRCC) patients with tumor thrombus. We observe tumor thrombus has increased tissue resident CD8+ T cells with a progenitor exhausted phenotype compared with the matched primary tumors. Remarkably, macrophages, malignant cells, endothelial cells and myofibroblasts from TTs exhibit enhanced remodeling of the extracellular matrix. The macrophages and malignant cells from primary tumors represent proinflammatory states, but also increase the expression of immunosuppressive markers compared to tumor thrombus. Finally, differential gene expression and interaction analyses reveal that tumor-stroma interplay reshapes the extracellular matrix in tumor thrombus associated with poor survival. Conclusions Our comprehensive picture of the ecosystem of ccRCC with tumor thrombus provides deeper insights into the mechanisms of tumor thrombus formation, which may aid in the design of effective neoadjuvant therapy to promote downstaging of tumor thrombus and decrease the perioperative morbidity and mortality of thrombectomy.
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