1. Prognostic Stratification Based on HIF-1 Signaling for Evaluating Hypoxic Status and Immune Infiltration in Pancreatic Ductal Adenocarcinomas.
- Author
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Zhuang H, Wang S, Chen B, Zhang Z, Ma Z, Li Z, Liu C, Zhou Z, Gong Y, Huang S, Hou B, Chen Y, and Zhang C
- Subjects
- Biomarkers, Tumor metabolism, Carcinoma, Pancreatic Ductal immunology, Carcinoma, Pancreatic Ductal metabolism, Carcinoma, Pancreatic Ductal therapy, Clinical Decision-Making, Gene Expression Regulation, Neoplastic, Humans, Hypoxia-Inducible Factor 1 metabolism, Lymphocytes, Tumor-Infiltrating immunology, Pancreatic Neoplasms immunology, Pancreatic Neoplasms metabolism, Pancreatic Neoplasms therapy, Predictive Value of Tests, Prognosis, Reproducibility of Results, Signal Transduction, Tumor Escape, Biomarkers, Tumor genetics, Carcinoma, Pancreatic Ductal genetics, Gene Expression Profiling, Hypoxia-Inducible Factor 1 genetics, Pancreatic Neoplasms genetics, Transcriptome, Tumor Hypoxia, Tumor Microenvironment immunology
- Abstract
Pancreatic ductal adenocarcinoma (PDAC) has a hypoxic and desmoplastic tumor microenvironment (TME), leading to treatment failure. We aimed to develop a prognostic classifier to evaluate hypoxia status and hypoxia-related molecular characteristics of PDAC. In this study, we classified PDAC into three clusters based on 16 known hypoxia-inducible factor 1 (HIF-1)-related genes. Nine differentially expressed genes were identified to construct an HIF-1 score system, whose predictive efficacy was evaluated. Furthermore, we investigated oncogenic pathways and immune-cell infiltration status of PDAC with different scores. The C-index of the HIF-1score system for OS prediction in the meta-PDAC cohort and the other two validation cohorts were 0.67, 0.63, and 0.65, respectively, indicating that it had a good predictive value for patient survival. Furthermore, the area under the curve (AUC) of the receiver operating characteristic (ROC) curve of the HIF-1α score system for predicting 1-, 3-, and 4-year OS indicated the HIF-1α score system had an optimal discrimination of prognostic prediction for PDAC. Importantly, our model showed superior predictive ability compared to previous hypoxia signatures. We also classified PDAC into HIF-1 scores of low, medium, and high groups. Then, we found high enrichment of glycolysis, mTORC1 signaling, and MYC signaling in the HIF-1 score high group, whereas the cGMP metabolic process was activated in the low score group. Of note, analysis of public datasets and our own dataset showed a high HIF-1 score was associated with high immunosuppressive TME, evidenced by fewer infiltrated CD8
+ T cells, B cells, and type 1 T-helper cells and reduced cytolytic activity of CD8+ T cells. In summary, we established a specific HIF-1 score system to discriminate PDAC with various hypoxia statuses and immune microenvironments. For highly hypoxic and immunosuppressive tumors, a combination treatment strategy should be considered in the future., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Zhuang, Wang, Chen, Zhang, Ma, Li, Liu, Zhou, Gong, Huang, Hou, Chen and Zhang.)- Published
- 2021
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