Significance of Immunogenic Cell Death-Related Prognostic Gene Signature in Cervical Cancer Prognosis and Anti-Tumor Immunity

Abstract

Background

Immunogenic cell death (ICD) can reshape the immune microenvironment of tumors. Driven by stressful pressure, by directly destroying tumor cells and activating the body’s adaptive immunity, ICD acts as a modulator of cell death, enabling the body to generate an anti-tumor immune response that produces a more effective therapeutic effect, while tumor cells are driven to kill. Hence, this research aimed to find and evaluate ICD-related genetic signatures as cervical cancer (CC) prognostic factors.

Methods

Data of CC patients from the Tumor Genome Atlas (TCGA) were used as the basis to obtain immunogenic cell-death-related prognostic genes (IPGs) in patients with CC, using the least absolute shrinkage and selection operator and Cox regression screening, and the IPGs scoring system was constructed to classify patients into high- and low-risk groups, with the Gene Expression Omnibus (GEO) dataset as the validation group. Finally, the difference analysis of single-sample gene set enrichment analysis, tumor microenvironment (TME), immune cells, tumor mutational burden, and chemotherapeutic drug sensitivity between the high-risk and low-risk groups was investigated.

Results

A prognostic model with four IPGs (PDIA3, CASP8, IL1, and LY96) was developed, and it was found that the group of CC patients with a higher risk score of IPGs expression had a lower survival rate. Single and multifactor Cox regression analysis also showed that this risk score was a reliable predictor of overall survival. In comparison to the low-risk group, the high-risk group had lower TME scores and immune cell infiltration, and gene set variation analysis showed that immune-related pathways were more enriched in the high-risk group.

Conclusion

A risk model constructed from four IPGs can independently predict the prognosis of CC patients and recommend more appropriate immunotherapy strategies for patients.

Keywords:

• ICD
• cervical cancer
• immunity
• prognosis
• immunotherapy response

Abbreviations

ICD, Immunogenic cell death; CC, cervical cancer; TCGA, The Tumor Genome Atlas; IPGs, Immunogenic cell death-related prognostic genes; GEO, The Gene Expression Omnibus; TME, Tumor microenvironment; HR, Hazard ratio; IRG, Immunogenic death-related genes; DCs, Recruiting dendritic cells; CTL, Cytotoxic T lymphocyte; K-M, Kaplan-Meier; KEGG, Kyoto Encyclopedia of Genes and Genomes; LASSO, Least absolute shrinkage, and selection operator; ROC, Receiver operator characteristics; ssGSEA, Single sample gene set enrichment analysis; TIDE, Tumor Immune Dysfunction, and Exclusion; DEGs, Differentially expressed genes; CNVs, Copy number variants; DAMPs, Damage-associated molecular patterns; Tregs, Regulatory T cells; MDSCs, Myeloid-derived suppressor cells; CAFs, Cancer-associated fibroblasts.

Data Sharing Statement

The RNA sequencing profiles can be gained from The Cancer Genome Atlas (TCGA) (https://portal.gdc.cancer.gov/) and Gene Expression Omnibus (GEO) (https://www.ncbi.nlm.nih.gov/geo/). Further inquiries can be directed to the corresponding author.

Informed Consent Statement

This study was carried out in conformity with the Declaration of Helsinki, national and international regulations, and ethical standards. Both TCGA and GEO are open databases. The patients involved in the database have obtained ethical approval. Users can download relevant data for free for research and publish relevant articles. The Ethics Committee of Fujian Cancer Hospital reviewed and approved the studies involving human participants. The patients/participants provided their written informed consent to participate in this study.

Acknowledgments

This work was supported by the National Natural Science Foundation of China (81873045), Joint Funds for the Innovation of Science and Technology of Fujian province (2021Y9209), and the high-level talents training project of Fujian Cancer Hospital (2022YNG04). We are grateful for the fund.

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis, and interpretation, or all these areas; took part in drafting, revising, or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Disclosure

The authors declare that they have no conflicts of interest.

Additional information

Funding

This work was supported by the National Natural Science Foundation of China (81873045), Joint Funds for the Innovation of Science and Technology of Fujian province (2021Y9209), and the high-level talents training project of Fujian Cancer Hospital (2022YNG04).