Cited by 999Cancer Immunotherapy and BiomarkersGastric Cancer Management and OutcomesImmune cells in cancer

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Tumor Microenvironment Characterization in Gastric Cancer Identifies Prognostic and Immunotherapeutically Relevant Gene Signatures

Zeng, Dongqiang, Li, Meiyi, Zhou, Rui, Zhang, Jingwen, Sun, Huiying, Shi, Min, Bin, Jianping, Liao, Yulin, Rao, Jinjun, Liao, Wangjun·2019·Cancer Immunology Research

DOI 10.1158/2326-6066.cir-18-0436

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Abstract

Tumor microenvironment (TME) cells constitute a vital element of tumor tissue. Increasing evidence has elucidated their clinicopathologic significance in predicting outcomes and therapeutic efficacy. Nonetheless, no studies have reported a systematic analysis of cellular interactions in the TME. In this study, we comprehensively estimated the TME infiltration patterns of 1,524 gastric cancer patients and systematically correlated the TME phenotypes with genomic characteristics and clinicopathologic features of gastric cancer using two proposed computational algorithms. Three TME phenotypes were defined, and the TMEscore was constructed using principal component analysis algorithms. The high TMEscore subtype was characterized by immune activation and response to virus and IFNγ. Activation of transforming growth factor β, epithelial–mesenchymal transition, and angiogenesis pathways were observed in the low TMEscore subtype, which are considered T-cell suppressive and may be responsible for significantly worse prognosis in gastric cancer [hazard ratio (HR), 0.42; 95% confidence interval (CI), 0.33–0.54; P < 0.001]. Multivariate analysis revealed that the TMEscore was an independent prognostic biomarker, and its value in predicting immunotherapeutic outcomes was also confirmed (IMvigor210 cohort: HR, 0.63; 95% CI, 0.46–0.89; P = 0.008; GSE78220 cohort: HR, 0.25; 95% CI, 0.07–0.89; P = 0.021). Depicting a comprehensive landscape of the TME characteristics of gastric cancer may, therefore, help to interpret the responses of gastric tumors to immunotherapies and provide new strategies for the treatment of cancers.

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Background
eRNAs Identify Immune Microenvironment Patterns and Provide a Novel Prognostic Tool in Acute Myeloid Leukemia
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Background
Characterization of RNA modifications in gastric cancer to identify prognosis‐relevant gene signatures
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m6A Regulator-Based Methylation Modification Patterns Characterized by Distinct Tumor Microenvironment Immune Profiles in Rectal Cancer
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“In a recent study (10), the CIBERSORT algorithm and Microenvironment Cell Populations-counter method were applied to bulk transcriptomic data of GC patients by which the abundance of 22 types of immune cells and two types of stromal cells was estimated, and three TME phenotypes were eventually defined based on the lan…”
Method
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BackgroundSelf-citation
Retracted
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Background
m7G regulator-mediated methylation modification patterns define immune cell infiltration and patient survival
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Method
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“Previous studies based on meta-analysis of bulk expression data related to gastric adenocarcinomas have indicated that high proportions of CD8 T cells and M1 macrophages were associated with a more favorable prognosis of intestinal gastric cancer (Zeng et al., 2019).”
BackgroundResult
Identification of the expression patterns and potential prognostic role of m6A-RNA methylation regulators in Wilms Tumor
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Method
Characterization of DNA Damage Repair Related Signature and Molecular Feature in Low-Grade Gliomas to Aid Chemotherapy and Drug Discovery
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MethodSelf-citation
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“We defined the CAV score using a method similar to GGI (Sotiriou et al., 2006; Zeng et al., 2019): CAV score = Σ (PC1i + PC2i), which is the expression of CAV-related genes.”
Method
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“…(Bai et al. 2019; Gao et al. 2019; Li et al. 2017; Liu et al. 2018; Yan et al. 2019; Yao et al. 2019; Zhang et al. 2020a, b) and immune cells fraction (Zeng et al. 2019; Zhou et al. 2019; Zhang et al. 2020a, b) existing in or influencing the many carcinomas” tumorigenesis, progress and therapy.”
Background
Homeobox Protein BarH-like 1 Promotes Gastric Cancer Progression by Activating Coiled-Coil Domain-Containing Protein 178
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“…implicated in cancer progression and therapeutic responses, and differences in the compositions of resident cell types within the tumor microenvironment, including cytotoxic T cells, helper T cells, dendritic cells, and tumor-associated macrophages (TAM) have been reported in patients with GC [7].”
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Background
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Background
A novel M2-like tumor associated macrophages-related gene signature for predicting the prognosis and immunotherapy efficacy in gastric cancer
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“Tumor-associated macrophages (TAMs), the most abundant immune cells in the tumor microenvironment (TME), can be differentiated into M1 and M2 types, which have become new therapeutic targets and prognostic indicators in the individualized treatment of malignant tumors [7, 27, 28].”
Background
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To describe the subsets of malignant epithelial cells in gastric cancer, their developmental trajectories and drug resistance characteristics
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“These cellular connections allow tumor cells to avoid immune detection and constitute the cytological basis of tumor development and metastasis [14, 15].”
Self-citation
Single-cell and bulk transcriptomic analyses uncover immune subtypes associated with programmed cell death features in intrahepatic cholangiocarcinoma
Zhang, T., Dou, D., Liu, Q., Xu, D., Wang, T., Liu, R., Lu, D., Zhao, X., Wang, S., & Zhang, H. (2026) · Scientific Reports · doi:10.1038/s41598-026-44332-8 · Cited by 1
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A Metabolic‐Epigenetic Axis of AARS1/IGF2BP3‐K280 Lactylation Sustains Endometrial Cancer Stemness and Recurrence
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“The final m6A score for each patient was defined using a method similar to GGI [ 39 ]: m6A score = ∑ (PC1 i + PC2 i ), where the i denotes each m6A enzyme.”
Identification and Validation of Co-Expressed Immune-Related Gene Signature Affecting the Pattern of Immune Infiltrating in Esophageal Cancer
Dong, B., Cheng, R., Zeng, H., Chen, L., & Zhou, L. (2022) · Combinatorial Chemistry & High Throughput Screening · doi:10.2174/1386207325666220705105906 · Cited by 1
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Association of RNA-modification “writer” genes with prognosis and response to immunotherapy in patients with low-grade glioma
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Xu, C., & Yi, X. (2023) · Frontiers in Genetics · doi:10.3389/fgene.2022.1065424 · Cited by 1
“To quantify the RNA modification patterns of individual tumor, we constructed a set of scoring system to evaluate the RNA modification pattern of individual patients with prostate cancer—the RM_Score (Zeng et al., 2019).”
Method
Bioinformatics-Led Identification of Potential Biomarkers and Inflammatory Infiltrates in Burn Injury
Niu, Z., Wei, G., Liang, H., Wang, X., Yang, W., Wei, G., Guo, J., Chen, Y., Tao, R., & Niu, J. (2023) · Journal of Burn Care & Research · doi:10.1093/jbcr/irad050 · Cited by 2
Molecular Expression and Prognostic Implications of Krüppel-Like Factor 3 (KLF3) in Clear Cell Renal Cell Carcinoma
Wan, B., Zhang, W., Deng, X., Lu, Y., Zhang, Z., & Yang, Y. (2023) · Critical Reviews in Eukaryotic Gene Expression · doi:10.1615/critreveukaryotgeneexpr.2023049010 · Cited by 1
Identification of subtype-specific master regulatory long non-coding RNAs of gastric cancer through a network-based approach
Jiang, L., Song, K., Li, X., Wang, Y., & Wang, X. (2023) · IEEE International Conference on Bioinformatics and Biomedicine (BIBM) · doi:10.1109/bibm58861.2023.10385532 · Cited by 1
“Notably, several molecular subtyping systems of GC based on gene expression profiles were introduced to dissect the GC heterogeneity with distinct biological characterization [2], [7] – [10].”
Background
Reliable prognostic definition and immunotherapy response prediction in bladder cancer, based on a novel aging-associated 5-gene signature model
Meng, W., Li, N., Chen, B., Zhang, H., Ma, L., & Guan, Y. (2024) · Translational Andrology and Urology · doi:10.21037/tau-23-422 · Cited by 1
“According to recent studies, it has been found that the TME has a crucial impact on tumorigenesis and progression (24,25).”
Background
DDOST is associated with tumor immunosuppressive microenvironment in cervical cancer
Mei, J., Pan, L., Huang, M., Bao, D., Gao, H., & Wang, D. (2024) · Discover Oncology · doi:10.1007/s12672-024-00927-z · Cited by 1
Identification of prognostic m6A modification patterns and score system in melanoma patients
Wang, F., Chen, P., Ouyang, S., Xiong, K., Liu, Z., & Wang, Y. (2024) · Medicine · doi:10.1097/md.0000000000037950 · Cited by 1
“We then fig-ured out a formula according to previous research: m 6 Ascore= ∑(PC1i + PC2i), [24,25] where “ i ” represents the expression of significant m 6 A phenotype-related genes.”
Method
Dynamic single‐cell sequencing unveils the tumor microenvironment evolution of gastric cancer abdominal wall metastases during radiotherapy
Mao, Q., Wu, Z., Lai, Y., Wang, L., Zhao, Q., Xu, X., Lu, X., Qiu, W., Zhang, Z., Wu, J., et al. (2024) · Cancer Science · doi:10.1111/cas.16308 · Cited by 1
Self-citation
Integrative Multi-Omics Analysis Reveals the Molecular Characteristics, Tumor Microenvironment, and Clinical Significance of Ubiquitination Mechanisms in Lung Adenocarcinoma
Long, D., Xue, Y., Yu, X., Qin, X., Chen, J., Luo, J., Ma, K., Wei, L. S., & Li, X. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26136501 · Cited by 1
m6A ‐Mediated Methylation Patterns and Their Association With Obstructive Sleep Apnea in Lung Adenocarcinoma
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“PCA was used to create m6A-associated gene signatures based on principal components 1 and 2, defining the m6A score similar to the Genomic Grade Index [35, 36].”
Self-citation
Analysis of Multi-Layer RNA Modification Patterns for the Characterization of Tumor Immune Microenvironment in Hepatocellular Carcinoma
Xing, J., Shen, S., Dong, Z., Hu, X., Xu, L., Liu, X., Li, Q., Zhang, Y., Cui, G., & Yu, Z. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.761391 · Cited by 1
“Finally, the RNA modification score was defined using a method similar to that used in analyzing gene-gene interactions (GGIs):WM-Score Σ (PC1i + PC2i), which is defined as the expression of final RNA modification phenotype-related genes (Sotiriou et al., 2006; Zeng et al., 2019).”
Method
Identification of a Four Cancer Stem Cell-Related Gene Signature and Establishment of a Prognostic Nomogram Predicting Overall Survival of Pancreatic Adenocarcinoma
Li, S., Chen, R., Luo, W., Lin, J., Chen, Y., Wang, Z., Lin, W., Li, B., Wang, J., & Yang, J. (2022) · Combinatorial Chemistry & High Throughput Screening · doi:10.2174/1386207325666220113142212 · Cited by 1
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Identification of a polycomb group-related gene signature for predicting prognosis and immunotherapy efficacy in lung adenocarcinoma
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“In recent years, tumor microenvironment (TME) has emerged as a critical factor in tumorigenesis and progression (39,40).”
N1-Methyladenosine (m1A) Regulator-Mediated Methylation Modification Modes and Tumor Microenvironment Infiltration Characteristics in Head and Neck Squamous Cell CarcinomasPreprint
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ESM1/VEGFα/ERK signaling axis augments cell proliferation and tumor angiogenesis in human cervical squamous cell carcinomaPreprint
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Comprehensive Analysis of circRNA-associated Competing Endogenous RNA Networks and Immune Infiltration in Gastric CancerPreprint
Xu, B., Zheng, E., Huang, Y., Zheng, L., Lan, Q., Zhou, X., Geng, X., Wang, Y., Wang, X., & Pan, W. (2021) · Research Square · doi:10.21203/rs.3.rs-805632/v1
Understanding the Interplay Between the Tumor Immune Microenvironment and Genetic Alterations in Thoracic Malignancies
Pasello, G., Felley‐Bosco, E., & Remon, J. (2022) · Frontiers research topics · doi:10.3389/978-2-88974-818-1
Typical Tumor Immune Microenvironment Status Determine Prognosis in Lung AdenocarcinomaPreprint
Ren, C., Li, J., Zhou, Y., Zhang, S., & Wang, Q. (2021) · SSRN Electronic Journal · doi:10.2139/ssrn.3922636
The pan-cancer landscape of crosstalk between chemokines and the tumor immune microenvironmentPreprint
Wuguo, T., Lingli, W., Jian-jie, Z., & Donglin, L. (2022) · Research Square · doi:10.21203/rs.3.rs-1643955/v1
Characterization of Immune Microenvironment Infiltration and m 6A Regulator-Mediated RNA Methylation Modification Patterns in OsteoarthritisPreprint
Ouyang, Y., Tu, Y., Chen, S., Min, H., Wen, Z., Zheng, G., Wan, T., Fan, H., Yang, W., & Sun, G. (2022) · SSRN Electronic Journal · doi:10.2139/ssrn.4133885
CD8+ T Cell/Cancer-Associated Fibroblasts Ratio Stratifies Prognostic and Predictive Responses to Immunotherapy Across Multiple Cancer TypesPreprint
Zheng, X., Jiang, K., Xiao, W., Zeng, D., Zeng, D., Bai, J., Chen, X., Li, P.-S., Zhang, L., Zhang, L., et al. (2022) · SSRN Electronic Journal · doi:10.2139/ssrn.4141239
Self-citation
Identification of Prognostic Gene Expression Signatures Based on Tumor Microenvironment Characterization of Gastric CancerPreprint
Sang, Q., Dai, W., Yu, J., Chen, Y., Fan, Z., Liu, J., Li, F., Li, J., Wu, X., Hou, J., et al. (2022) · SSRN Electronic Journal · doi:10.2139/ssrn.4104376
TOP2A is a potential biomarker and promotes platinum drug resistance in ovarian cancer: a bioinformatics and experimental analysisPreprint
Zheng, X., Liu, W., Zhang, K., Chen, L., Zhao, S., Yan, Y., Tian, W., Xue, F., & Wang, Y. (2022) · Research Square · doi:10.21203/rs.3.rs-1954513/v1
Analysis of Clinical Implications and Immune Landscape in Prognostic Model based on Immune Cell Signatures for Lung Adenocarcinoma PatientsPreprint
Gao, W., Zhou, Y., Zong, Y., Wang, N., Nanding, A., & Yu, Y. (2022) · Research Square · doi:10.21203/rs.3.rs-2040653/v1
Comprehensive Analysis of Cuproptosis-related genes in prognosis, tumor microenvironment infiltration, and Immunotherapy response in gastric cancerPreprint
Nie, H., Wang, H., Zhang, M., Ning, Y., Chen, X., Zhang, Z., Hu, X., Zhao, Q., Chen, P., Fang, J., et al. (2022) · Research Square · doi:10.21203/rs.3.rs-2018538/v1
High levels of m6A methylation and histone acetylation modification patterns contribute to the survival of LUAD patientsPreprint
Jia, L.-G., Gao, Z., & Chen, J. (2022) · Research Square · doi:10.21203/rs.3.rs-2199422/v1
DNA5mC Regulator-Mediated Molecular Clusters and Tumor Microenvironment Signatures in Glioblastoma
Yu, X., Che, Y., Li, W., Zhang, P., Yu, Y., Chen, J., Gong, T., & Cao, F. (2022) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2022.1055567
“represents the expression of DNA5mC regulator related genes (Sotiriou et al., 2006; Zeng et al., 2019).”
Background
Comprehensive Bioinformatics Analysis Identifies a Novel Cellular Senescence Associated Factor-Related Signature to Predict Prognosis and Efficacy of Immunotherapy in Lung Squamous Cell CarcinomaPreprint
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Identification and Prognostic Analysis of Ferroptosis-related Genes to Predict The Progression of Lung Squamous Cell CarcinomaPreprint
Guo, D., Feng, Y., Liu, P., Yang, S., Zhao, W., & Li, H. (2022) · Research Square · doi:10.21203/rs.3.rs-2310596/v1
Role of Neuromodulators in Regulation of the Tumor Microenvironment of Gastric and Colorectal Cancers
Chakroborty, D., & Sarkar, C. (2022) · Interdisciplinary cancer research · doi:10.1007/16833_2022_93
m5C related-regulator-mediated methylation modification patterns and prognostic significance in breast cancerPreprint
Wu, X., Li, C., Luo, Y., Ren, X., Chen, C., Zhang, G., Wang, Z., & Wang, S. (2023) · Research Square · doi:10.21203/rs.3.rs-2534342/v1
Investigation and verification of GAMAP6 as a robust biomarker for prognosis and tumor immunity in lung adenocarcinomaPreprint
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Liu, Z., Chen, P., Ouyang, S., Xiong, K., Wang, Q., Zhou, M., & Wang, Y. (2023) · Research Square · doi:10.21203/rs.3.rs-2575508/v1
Association of an eight-gene signature prognosis model with tumor immunity in medulloblastomaPreprint
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Targeting Gastric Cancer Cells using Nanoparticles to Improve Diagnosis and Treatment Outcomes while Minimizing Off-Target Toxicity
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Authors: Zeng, D., Li, M., Zhou, R., Zhang, J., Sun, H., Shi, M., Bin, J., Liao, Y., Rao, J., & Liao, W.
Affiliations: Nanfang Hospital (CN)
Southern Medical University (CN)
ORCID: Zeng, Dongqiang
Li, Meiyi
Zhou, Rui
Zhang, Jingwen
Sun, Huiying
Shi, Min
Bin, Jianping
Liao, Yulin
Liao, Wangjun
Venue: Cancer Immunology Research
Publisher: American Association for Cancer Research (AACR)
Published: 2019-05-01
Volume: 7
Issue: 5
Pages: 737-750
ISSN: 2326-6066 (ISSN-L)
2326-6074
DOI: 10.1158/2326-6066.cir-18-0436
OpenAlex: W2920600229
Semantic Scholar: 180648d1827a7e8c086f03b00ca69831a1ca538e
Cited by: 986
References: 76
Citations by year: 2026: 38 · 2025: 87 · 2024: 164 · 2023: 211 · 2022: 251 · 2021: 162 · 2020: 64 · 2019: 9
FWCI: 53.10
Type: journal article
Language: en
Open access: closed
Locations: Cancer Immunology Research (publishedVersion)
PubMed (publishedVersion)
Funders: National Natural Science Foundation of China (81772580)
Topics: Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
Health Sciences › Medicine › Oncology › Gastric Cancer Management and Outcomes
Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
Keywords: gastric cancer, tumor microenvironment, prognostic factors, immunotherapy response, immune cell infiltration, T cell suppression, epithelial-mesenchymal transition, angiogenesis, TGF-beta signaling, IFN-gamma response, gene expression signatures, IMvigor210
MeSH terms: Antineoplastic Agents, Immunological, Algorithms, Humans, Immunotherapy, Phenotype, Prognosis, Stomach Neoplasms, Gene Expression Regulation, Neoplastic, Tumor Microenvironment

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Tumor Microenvironment Characterization in Gastric Cancer Identifies Prognostic and Immunotherapeutically Relevant Gene Signatures

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