Prognostic Stratification Based on HIF-1 Signaling for Evaluating Hypoxic Status and Immune Infiltration in Pancreatic Ductal Adenocarcinomas
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 thre...
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Frontiers Media S.A.
2021
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oai:doaj.org-article:f01bb09807914c998608fb4ce4f0fc3a2021-12-03T04:51:47ZPrognostic Stratification Based on HIF-1 Signaling for Evaluating Hypoxic Status and Immune Infiltration in Pancreatic Ductal Adenocarcinomas1664-322410.3389/fimmu.2021.790661https://doaj.org/article/f01bb09807914c998608fb4ce4f0fc3a2021-12-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fimmu.2021.790661/fullhttps://doaj.org/toc/1664-3224Pancreatic 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.Hongkai ZhuangHongkai ZhuangShujie WangBo ChenZedan ZhangZuyi MaZhenchong LiChunsheng LiuZixuan ZhouYuanfeng GongShanzhou HuangBaohua HouYajin ChenChuanzhao ZhangFrontiers Media S.A.articlePDACHIF-1hypoxiaICBimmunosuppressionimmune infiltrationImmunologic diseases. AllergyRC581-607ENFrontiers in Immunology, Vol 12 (2021) |
| institution |
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| collection |
DOAJ |
| language |
EN |
| topic |
PDAC HIF-1 hypoxia ICB immunosuppression immune infiltration Immunologic diseases. Allergy RC581-607 |
| spellingShingle |
PDAC HIF-1 hypoxia ICB immunosuppression immune infiltration Immunologic diseases. Allergy RC581-607 Hongkai Zhuang Hongkai Zhuang Shujie Wang Bo Chen Zedan Zhang Zuyi Ma Zhenchong Li Chunsheng Liu Zixuan Zhou Yuanfeng Gong Shanzhou Huang Baohua Hou Yajin Chen Chuanzhao Zhang Prognostic Stratification Based on HIF-1 Signaling for Evaluating Hypoxic Status and Immune Infiltration in Pancreatic Ductal Adenocarcinomas |
| description |
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. |
| format |
article |
| author |
Hongkai Zhuang Hongkai Zhuang Shujie Wang Bo Chen Zedan Zhang Zuyi Ma Zhenchong Li Chunsheng Liu Zixuan Zhou Yuanfeng Gong Shanzhou Huang Baohua Hou Yajin Chen Chuanzhao Zhang |
| author_facet |
Hongkai Zhuang Hongkai Zhuang Shujie Wang Bo Chen Zedan Zhang Zuyi Ma Zhenchong Li Chunsheng Liu Zixuan Zhou Yuanfeng Gong Shanzhou Huang Baohua Hou Yajin Chen Chuanzhao Zhang |
| author_sort |
Hongkai Zhuang |
| title |
Prognostic Stratification Based on HIF-1 Signaling for Evaluating Hypoxic Status and Immune Infiltration in Pancreatic Ductal Adenocarcinomas |
| title_short |
Prognostic Stratification Based on HIF-1 Signaling for Evaluating Hypoxic Status and Immune Infiltration in Pancreatic Ductal Adenocarcinomas |
| title_full |
Prognostic Stratification Based on HIF-1 Signaling for Evaluating Hypoxic Status and Immune Infiltration in Pancreatic Ductal Adenocarcinomas |
| title_fullStr |
Prognostic Stratification Based on HIF-1 Signaling for Evaluating Hypoxic Status and Immune Infiltration in Pancreatic Ductal Adenocarcinomas |
| title_full_unstemmed |
Prognostic Stratification Based on HIF-1 Signaling for Evaluating Hypoxic Status and Immune Infiltration in Pancreatic Ductal Adenocarcinomas |
| title_sort |
prognostic stratification based on hif-1 signaling for evaluating hypoxic status and immune infiltration in pancreatic ductal adenocarcinomas |
| publisher |
Frontiers Media S.A. |
| publishDate |
2021 |
| url |
https://doaj.org/article/f01bb09807914c998608fb4ce4f0fc3a |
| work_keys_str_mv |
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| _version_ |
1718373963573231616 |