Dataset Information

Pyroptosis-Mediated Molecular Subtypes are Characterized by Distinct Tumor Microenvironment Infiltration Characteristics in Breast Cancer.

ABSTRACT:

Background

Numerous reports have highlighted that pyroptosis is closely linked to tumorigenesis and drug resistance of tumors. However, the potential role of pyroptosis in regulating immune cell infiltration in tumor microenvironment (TME) remains unclear.

Methods

Here, we performed consensus clustering analysis based on the expression of 10 typical pyroptosis-related regulators (PRRs) to construct pyroptosis-mediated tumor pattern clusters and pyroptosis-related gene signature in breast cancer (BC). GSVA combined with ssGSEA methods were applied to evaluate the differences in biological pathway and immune cell infiltration level, respectively. The PCA method was employed to construct the pyro-score to quantify the pyroptosis pattern level of individual BC patient.

Results

We determined three distinct pyro-clusters among 1852 BC samples, which exhibited different survival outcomes and enriched biological processes. The TME features demonstrated that these three clusters corresponded to three established immune profiles: immune-desert, immune-excluded and immune-inflamed phenotype, respectively. Based on pyroptosis-related signature genes, we constructed the pyro-score and stratified BC patients into high and low pyro-score group. Patients with high pyro-score exhibited favorable outcome and increased infiltration of immune cells. Further investigation revealed that high pyro-score was also related to high expression of immunosuppressive molecules, decreased tumor mutation burden (TMB) and high rate of mutation in significantly mutated genes (SMGs) (eg, PIK3CA and CDH1).

Conclusion

This research emphasizes the indispensable role of pyroptosis in TME complexity and diversity. Assessing the pyroptosis pattern level of individual BC patient will assist us in better understanding TME features and directing more effective immunotherapeutic approaches.

SUBMITTER: Xu L

PROVIDER: S-EPMC8779844 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundBrain tumor ranks as the most devastating cancer type. The complex tumor immune microenvironment prevents brain tumor from receiving therapeutic benefits. The purpose of this study was to stratify brain tumors based on their distinct immune infiltration signatures to facilitate better clinical decision making and prognosis prediction.MethodsWe developed a deep learning model to characterize immune infiltration from transcriptome. The developed model was applied to distill expression signatures of transcriptome of brain tumor samples. We performed molecular subtyping with the extracted expression signatures to unveil brain tumor subtypes. Computational methods, including gene set enrichment analysis, Kaplan-Meier survival and multivariate Cox regression analyses, were employed.ResultsWe identified two distinctive subtypes (i.e. C1/2) of brain tumor featured by distinct immune infiltration signatures. The C1 subtype is characterized by protective immune infiltration signatures, including high infiltration of CD8+ T cells and activation of CX3CL1. The C2 subtype has an extensive infiltration of tumor-associated macrophages and microglia, and was enriched with immune suppressive, wound-healing, and angiogenic signatures. The C1 subtype had significantly better prognosis as compared with C2 (Log-rank test, HR: 2.5, 95% CI: 2.2 - 2.7; P = 8.2e-78). This difference remained statistically significant (multivariate Cox model, HR: 2.2, 95% CI: 1.7 - 2.9; P = 3.7e-10) by taking into account age, gender, recurrent/secondary status at sampling time, tumor grade, histology, radio-chemotherapy, IDH mutation, MGMT methylation, and co-deletion of 1p and 19q. This finding was validated in six datasets. The C2 subtype of glioblastoma patients with IDH mutation has poor survival analogous to those without IDH mutation (Log-rank test, adjusted P = 0.8), while C1 has favorable prognosis as compared with glioblastoma of C2 subtype with IDH mutation (Log-rank test, adjusted P = 1.2e-3) or without IDH mutation (Log-rank test, adjusted P = 1.3e-6).ConclusionsWe identified two distinctive subtypes of brain tumor with different immune infiltration signatures, which might be helpful as an independent prognosticator for brain tumor.