Identification and validation of stromal-tumor microenvironment-based subtypes tightly associated with PD-1/PD-L1 immunotherapy and outcomes in patients with gastric cancer
Abstract Background Immunotherapies targeting programmed cell death 1 (PD-1) and programmed death-ligand 1 (PD-L1) have been approved for gastric cancer (GC) patients. However, a large proportion of patients with T-cell-inflamed tumor microenvironment do not respond to the PD-1/PD-L1 blockade. The s...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2020-03-01
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| Series: | Cancer Cell International |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s12935-020-01173-3 |
| _version_ | 1818934475815387136 |
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| author | Qianqian Ren Peng Zhu Hui Zhang Tianhe Ye Dehan Liu Zhao Gong Xiangwen Xia |
| author_facet | Qianqian Ren Peng Zhu Hui Zhang Tianhe Ye Dehan Liu Zhao Gong Xiangwen Xia |
| author_sort | Qianqian Ren |
| collection | DOAJ |
| description | Abstract Background Immunotherapies targeting programmed cell death 1 (PD-1) and programmed death-ligand 1 (PD-L1) have been approved for gastric cancer (GC) patients. However, a large proportion of patients with T-cell-inflamed tumor microenvironment do not respond to the PD-1/PD-L1 blockade. The stromal component of the tumor microenvironment has been associated with immunotherapy. This study aims to explore the clinical significance of the non-immune cells in the tumor microenvironment and their potential as biomarkers for immunotherapy. Methods A total of 383 patients with GC from the Cancer Genome Atlas (TCGA) cohort, 300 patients with GC from the GSE62254 cohort in Gene Expression Omnibus (GEO) were included in the study. A stromal score was generated using the ESTIMATE algorithm, and the likelihood of response to PD-1/PD-L1 immunotherapy of GC patients was predicted using the TIDE algorithm. The prognostic value of the stromal score from GC cases was evaluated by the Kaplan–Meier method and Cox regression analysis. Gene set enrichment analysis (GSEA) was also conducted. Results The stromal score showed significant differences in different molecular subtypes and T stages. Multivariate analyses further confirmed that the stromal score was an independent indicator of overall survival (OS) in the two cohorts. The low stromal score group showed higher tumor mutation burden (TMB) and micro-satellite instability (MSI), and was more sensitive to immune checkpoint inhibitor according to the TIDE algorithm. Activation of the transforming growth factor and epithelial–mesenchymal transition were observed in the high stromal score subtype, which is associated with T-cell suppression, and may be responsible for resistance to PD-1/PD-L1 therapy. BPIFB2 was confirmed as a hub gene relevant to immunotherapy. Conclusion The stromal score was associated with cancer progression and molecular subtypes, and may serve as a novel biomarker for predicting the prognosis and response to immunotherapy in patients with GC. |
| first_indexed | 2024-12-20T05:04:52Z |
| format | Article |
| id | doaj.art-b7cff39cff814e7ba842934be3bd4480 |
| institution | Directory Open Access Journal |
| issn | 1475-2867 |
| language | English |
| last_indexed | 2024-12-20T05:04:52Z |
| publishDate | 2020-03-01 |
| publisher | BMC |
| record_format | Article |
| series | Cancer Cell International |
| spelling | doaj.art-b7cff39cff814e7ba842934be3bd44802022-12-21T19:52:26ZengBMCCancer Cell International1475-28672020-03-0120111310.1186/s12935-020-01173-3Identification and validation of stromal-tumor microenvironment-based subtypes tightly associated with PD-1/PD-L1 immunotherapy and outcomes in patients with gastric cancerQianqian Ren0Peng Zhu1Hui Zhang2Tianhe Ye3Dehan Liu4Zhao Gong5Xiangwen Xia6Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Hepatobiliary SurgeryDepartment of Internal Medicine, Wuhan Hankou HospitalDepartment of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Hepatobiliary SurgeryDepartment of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and TechnologyAbstract Background Immunotherapies targeting programmed cell death 1 (PD-1) and programmed death-ligand 1 (PD-L1) have been approved for gastric cancer (GC) patients. However, a large proportion of patients with T-cell-inflamed tumor microenvironment do not respond to the PD-1/PD-L1 blockade. The stromal component of the tumor microenvironment has been associated with immunotherapy. This study aims to explore the clinical significance of the non-immune cells in the tumor microenvironment and their potential as biomarkers for immunotherapy. Methods A total of 383 patients with GC from the Cancer Genome Atlas (TCGA) cohort, 300 patients with GC from the GSE62254 cohort in Gene Expression Omnibus (GEO) were included in the study. A stromal score was generated using the ESTIMATE algorithm, and the likelihood of response to PD-1/PD-L1 immunotherapy of GC patients was predicted using the TIDE algorithm. The prognostic value of the stromal score from GC cases was evaluated by the Kaplan–Meier method and Cox regression analysis. Gene set enrichment analysis (GSEA) was also conducted. Results The stromal score showed significant differences in different molecular subtypes and T stages. Multivariate analyses further confirmed that the stromal score was an independent indicator of overall survival (OS) in the two cohorts. The low stromal score group showed higher tumor mutation burden (TMB) and micro-satellite instability (MSI), and was more sensitive to immune checkpoint inhibitor according to the TIDE algorithm. Activation of the transforming growth factor and epithelial–mesenchymal transition were observed in the high stromal score subtype, which is associated with T-cell suppression, and may be responsible for resistance to PD-1/PD-L1 therapy. BPIFB2 was confirmed as a hub gene relevant to immunotherapy. Conclusion The stromal score was associated with cancer progression and molecular subtypes, and may serve as a novel biomarker for predicting the prognosis and response to immunotherapy in patients with GC.http://link.springer.com/article/10.1186/s12935-020-01173-3Gastric cancerStromal cells infiltrationStromal scoreOverall survivalPD-1/PD-L1 therapy |
| spellingShingle | Qianqian Ren Peng Zhu Hui Zhang Tianhe Ye Dehan Liu Zhao Gong Xiangwen Xia Identification and validation of stromal-tumor microenvironment-based subtypes tightly associated with PD-1/PD-L1 immunotherapy and outcomes in patients with gastric cancer Cancer Cell International Gastric cancer Stromal cells infiltration Stromal score Overall survival PD-1/PD-L1 therapy |
| title | Identification and validation of stromal-tumor microenvironment-based subtypes tightly associated with PD-1/PD-L1 immunotherapy and outcomes in patients with gastric cancer |
| title_full | Identification and validation of stromal-tumor microenvironment-based subtypes tightly associated with PD-1/PD-L1 immunotherapy and outcomes in patients with gastric cancer |
| title_fullStr | Identification and validation of stromal-tumor microenvironment-based subtypes tightly associated with PD-1/PD-L1 immunotherapy and outcomes in patients with gastric cancer |
| title_full_unstemmed | Identification and validation of stromal-tumor microenvironment-based subtypes tightly associated with PD-1/PD-L1 immunotherapy and outcomes in patients with gastric cancer |
| title_short | Identification and validation of stromal-tumor microenvironment-based subtypes tightly associated with PD-1/PD-L1 immunotherapy and outcomes in patients with gastric cancer |
| title_sort | identification and validation of stromal tumor microenvironment based subtypes tightly associated with pd 1 pd l1 immunotherapy and outcomes in patients with gastric cancer |
| topic | Gastric cancer Stromal cells infiltration Stromal score Overall survival PD-1/PD-L1 therapy |
| url | http://link.springer.com/article/10.1186/s12935-020-01173-3 |
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