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Published on: January 22, 2013
Pyroptosis-Related Subtypes Predict the Response of Clear Cell Renal Cell Carcinoma to Targeted Therapy
Jinpeng Ma1,2, Zhijian Kang1,2, Guang Yang3
1NHC Key Laboratory of Molecular Probes and Targeted Diagnosis and Therapy, Harbin Medical University, 150001 Harbin, Heilongjiang, China.
Background:
Pyroptosis plays a crucial role in anti-tumor immunity and in formation of the immune microenvironment. However, whether pyroptosis is involved in the progression of clear cell renal cell carcinoma (ccRCC) is still unclear. Personalized treatment of ccRCC requires detailed molecular classification to inform a specific therapy.
Methods:
Molecular subtyping of ccRCC was performed based on consensus clustering of pyroptosis-related genes. The characteristics of these molecular subtypes were explored at the genome, transcriptome and protein levels. Single-cell RNA sequencing and CIBERSORT analysis were used to analyse the immune microenvironment of ccRCC, while Lasso regression was used to develop a prediction model based on hub genes. Expression of the pyroptosis-related gene GSDMB was also investigated at the tissue and cellular levels.
Results:
Two molecular subtypes were identified based on the clustering of pyroptosis-related genes. Cluster 1 was associated with activation of classical oncogenic pathways, especially the angiogenesis pathway. Cluster 2 was associated with activation of immune-related pathways and high levels of immunosuppressive cells, exhausted CD8+ T cells, and tumor-associated fibroblast infiltration. Clusters 1 and 2 were thus defined as the angiogenic and inflamed subtypes, respectively. The two subtypes were predictive of the response of ccRCC to anti-angiogenic therapy and immunotherapy, with Cluster 1 patients benefiting from anti-angiogenic therapy and Cluster 2 patients showing better response to anti-PD1 inhibitor therapy. Furthermore, a 9-gene expression signature (HJURP, NUF2, KIF15, MELK, TPX2, PLK1, CDCA3, CTLA4, FOXP3) was identified that could predict outcome and response to immune checkpoint blockade therapy in test cohorts. Finally, GSDMB was found to be involved in the development of renal clear cell carcinoma.
Conclusions:
These results on pyroptosis-related genes in ccRCC provide a theoretical basis for understanding molecular heterogeneity and for the development of individualized treatment strategies.
Insights
Pyroptosis influences clear cell renal cell carcinoma (ccRCC) progression and immune microenvironment. This study identifies two ccRCC subtypes, predicting responses to anti-angiogenic therapy and immunotherapy.
Area of Science:
- Oncology
- Immunology
- Genetics
Background:
- Pyroptosis is key in anti-tumor immunity and immune microenvironment formation.
- The role of pyroptosis in clear cell renal cell carcinoma (ccRCC) progression remains unclear.
- Personalized ccRCC treatment necessitates detailed molecular classification.
Purpose of the Study:
- To investigate the involvement of pyroptosis in ccRCC progression.
- To perform molecular subtyping of ccRCC based on pyroptosis-related genes.
- To explore the characteristics of these subtypes and develop predictive models for treatment response.
Main Methods:
- Consensus clustering of pyroptosis-related genes for ccRCC molecular subtyping.
- Analysis of genomic, transcriptomic, and proteomic characteristics of subtypes.
- Single-cell RNA sequencing, CIBERSORT, and Lasso regression for immune microenvironment and predictive model development.
- Investigation of Gasdermin B (GSDMB) expression in ccRCC tissues and cells.
Main Results:
- Two ccRCC subtypes identified: angiogenic (Cluster 1) and inflamed (Cluster 2).
- Angiogenic subtype associated with oncogenic pathways; inflamed subtype with immune-related pathways and immunosuppressive cells.
- Subtypes predict response to anti-angiogenic therapy (Cluster 1) and anti-PD1 immunotherapy (Cluster 2).
- A 9-gene signature identified to predict ccRCC outcome and response to immune checkpoint blockade.
- Gasdermin B (GSDMB) implicated in ccRCC development.
Conclusions:
- Pyroptosis-related gene subtypes offer insights into ccRCC molecular heterogeneity.
- Findings provide a basis for developing individualized treatment strategies for ccRCC.
- Subtype-specific therapeutic strategies can improve patient outcomes.
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