scholarly journals The Immune Subtypes and Landscape of Gastric Cancer and to Predict Based on the Whole-Slide Images Using Deep Learning

2021 ◽  
Vol 12 ◽  
Author(s):  
Yan Chen ◽  
Zepang Sun ◽  
Wanlan Chen ◽  
Changyan Liu ◽  
Ruoyang Chai ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
T Cells ◽  
Deep Learning ◽  
Immune Cells ◽  
Gene Set Enrichment Analysis ◽  
Functional Enrichment ◽  
Resting Cells ◽  
M1 Macrophages ◽  
Immune Score ◽  
Subtype 3

BackgroundGastric cancer (GC) is a highly heterogeneous tumor with different responses to immunotherapy. Identifying immune subtypes and landscape of GC could improve immunotherapeutic strategies.MethodsBased on the abundance of tumor-infiltrating immune cells in GC patients from The Cancer Genome Atlas, we used unsupervised consensus clustering algorithm to identify robust clusters of patients, and assessed their reproducibility in an independent cohort from Gene Expression Omnibus. We further confirmed the feasibility of our immune subtypes in five independent pan-cancer cohorts. Finally, functional enrichment analyses were provided, and a deep learning model studying the pathological images was constructed to identify the immune subtypes.ResultsWe identified and validated three reproducible immune subtypes presented with diverse components of tumor-infiltrating immune cells, molecular features, and clinical characteristics. An immune-inflamed subtype 3, with better prognosis and the highest immune score, had the highest abundance of CD8+ T cells, CD4+ T–activated cells, follicular helper T cells, M1 macrophages, and NK cells among three subtypes. By contrast, an immune-excluded subtype 1, with the worst prognosis and the highest stromal score, demonstrated the highest infiltration of CD4+ T resting cells, regulatory T cells, B cells, and dendritic cells, while an immune-desert subtype 2, with an intermediate prognosis and the lowest immune score, demonstrated the highest infiltration of M2 macrophages and mast cells, and the lowest infiltration of M1 macrophages. Besides, higher proportion of EVB and MSI of TCGA molecular subtyping, over expression of CTLA4, PD1, PDL1, and TP53, and low expression of JAK1 were observed in immune subtype 3, which consisted with the results from Gene Set Enrichment Analysis. These subtypes may suggest different immunotherapy strategies. Finally, deep learning can predict the immune subtypes well.ConclusionThis study offers a conceptual frame to better understand the tumor immune microenvironment of GC. Future work is required to estimate its reference value for the design of immune-related studies and immunotherapy selection.

Immune Infiltration in Gastric Cancer Microenvironment and Its Clinical Significance

2020 ◽  
Author(s):  
An Zhi Zhang ◽  
Xin Yuan ◽  
Ya Li ◽  
Yu Fang Xie ◽  
Jiang Fen Li ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
T Cells ◽  
Immune Cells ◽  
Expression Profiles ◽  
Tnm Staging ◽  
Functional Enrichment ◽  
Cancer Tissue ◽  
Fuhrman Grade ◽  
Cytokine Activation ◽  
Immune Related Genes

Abstract Background In recent years, immunotherapy has developed rapidly and has gradually become one of the important methods for treatment of gastric cancer. The research on immune cells and immune-related genes in the tumor microenvironment greatly encourages the development of immunotherapy. Methods : The devolution algorithm (CIBERSORT) was applied to infer the proportion of 22 immune infiltrating cells based on gene expression profiles of gastric cancer tissue, which were downloaded from TCGA and GEO databases. The TCGA database was utilized to analyze the differential expression of immune-related genes, and explore the potential molecular functions of these genes.ResultsWe have observed the enrichment of multiple immune cells in the microenvironment of gastric cancer. Some of these cells are closely related to Fuhrman grade and TNM staging. Survival analysis showed that the infiltration level of CD8 + T cells, activated CD4 + memory T cells and M2 macrophages was significantly related to the prognosis of gastric cancer patients. The functional enrichment analysis of immune-related genes revealed that these genes were mainly associated with cytokine activation and response. Four significant modules were screened by PPI network and 20 key genes were screened from the modules, and the expression levels of CALCR and PTH1R are strikingly related to the prognosis of gastric cancer patients.ConclusionsThe type and number of infiltrating immune cells in the microenvironment of gastric cancer, as well as immune-related genes are closely related to tumor progression, and can be used as important indicators for patient prognosis assessment.

scholarly journals A pan-cancer analysis revealing the role of TIGIT in tumor microenvironment

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Jie Wen ◽  
Xueyi Mao ◽  
Quan Cheng ◽  
Zhixiong Liu ◽  
Fangkun Liu
Keyword(s):  
T Cells ◽  
Immune Cells ◽  
Immune Checkpoint ◽  
Expression Patterns ◽  
Gene Set Enrichment Analysis ◽  
Functional Enrichment ◽  
Receptor Interaction ◽  
Mmr Genes ◽  
Potential Biomarker ◽  
Cancer Types

AbstractT cell immunoreceptor with immunoglobulin and ITIM domain (TIGIT), an immune checkpoint, plays a pivotal role in immune suppression. However its role in tumor immunity and correlation with the genetic and epigenetic alterations remains unknown. Here, we comprehensively analyzed the expression patterns of the TIGIT and its value of prognostic prediction among 33 types of cancers based on the data collected from The Cancer Genome Atlas (TCGA) and the Genotype-Tissue Expression projects (GTEx). Furthermore, the correlations of TIGIT with pathological stages, tumor-infiltrating immune cells (TIICs), signatures of T cells subtypes, immune checkpoint genes, the degree of Estimation of STromal and Immune cells in MAlignant Tumor tissues using the Expression data (ESTIMATE), tumor mutation burden (TMB), microsatellite instability (MSI), mismatch repair (MMR) genes, and DNA methyltransferases (DNMTs) were also explored. Gene functional enrichment was conducted by Gene Set Enrichment Analysis (GSEA). Our results showed that the expression of TIGIT was upregulated in most of the cancer types. Cox regression model showed that high expression of TIGIT in tumor samples correlates with poor prognosis in KIRC, KIRP, LGG, UVM, and with favorable prognosis in BRCA, CECS, HNSC, SKCM. TIGIT expression positively correlated with advanced stages, TIICs, the signatures of effector T cells, exhausted T cells, effector Tregs and the degree of ESTIMATE in KIRC, KIRP and UVM. TIGIT expression also positively correlated with CTLA4, PDCD1 (PD-1), CD274 (PD-L1), ICOS in most of the cancer types. Furthermore, the expression of TIGIT was correlated with TMB, MSI, MMR genes and DNMTs in different types of cancers. GSEA analysis showed that the expression of TIGIT was related to cytokine-cytokine receptor interaction, allograft rejection, oxidative phosphorylation. These findings suggested that TIGIT could serve as a potential biomarker for prognosis and a novel target for immunotherapies in cancers.

scholarly journals Upregulation of B3GNT3 Correlates With Poor Prognosis and Decreased Immune Cell Infiltration In Pancreatic Adenocarcinoma

2021 ◽  
Author(s):  
Long-Jiang Chen ◽  
Lu-Lu Zhai ◽  
Wei Wang ◽  
Lun Wu ◽  
Li-Chao Yao ◽  
...  
Keyword(s):  
T Cells ◽  
Signaling Pathway ◽  
Pancreatic Adenocarcinoma ◽  
Immune Cells ◽  
Immune Cell ◽  
Enrichment Analysis ◽  
Transport Processes ◽  
Gene Set Enrichment Analysis ◽  
Functional Enrichment ◽  
Activated T Cells

Abstract While previous studies have suggested that B3GNT3 is associated with tumorigenesis and progression of several tumors, its expression level and clinical significance in pancreatic adenocarcinoma (PAAD) remains unclear. Our study aimed to investigate the role of B3GNT3 in PAAD. B3GNT3 RNA sequencing and clinicopathological data were collected from the TCGA, GEO and GTEx databases. We assessed the expression and prognostic value of B3GNT3 in PAAD using R program and attached packages. Additionally, we investigate the correlation between B3GNT3 expression and tumor-infiltrating immune cells using CIBERSORT and the “correlation” module of GEPIA. Finally, gene set enrichment analysis (GSEA) was used to elucidate B3GNT3 related signaling pathways in PAAD. Results showed that B3GNT3 expression was significantly higher in tumor tissues compared to normal tissues (P <0.05). Increased B3GNT3 expression was correlated with advanced histologic grade and stage (Ⅰ Vs Ⅱ). Patients with high B3GNT3 expression had a worse OS (HR = 1.713, P = 0.0005). Moreover, a negative correlation between increased B3GNT3 expression and immune infiltrating level of naive B cells, CD8 T cells, and CD4 memory activated T cells was revealed by CIBERSORT analysis. Then, further analysis verified the correlation using the “correlation” module of GEPIA. Finally, GSEA suggested that functional enrichment of B3GNT3 was mainly involved in pathways in cancer, p53 signaling pathway, TGF beta signaling pathway, catabolic and transport processes of proteins, etc. Collectively, these results suggested that overexpression of B3GNT3 might affect the infiltration of immune cells and could act as a potential prognostic biomarker of PAAD.

Infiltration Patterns of Immune Cells in Gastric Cancer and Their Clinical Correlation with Prognosis

2020 ◽  
Author(s):  
XiaoLi Wu ◽  
Hongbo Ma ◽  
YanYan Li
Keyword(s):  
Gastric Cancer ◽  
T Cells ◽  
Mast Cells ◽  
Nk Cells ◽  
Cancer Patients ◽  
Cd8 T Cells ◽  
Immune Cells ◽  
Immune Cell ◽  
M1 Macrophages ◽  
Gastric Cancer Patients

Abstract Abstract: Objective Gastric cancer is a malignant tumour that severely affects the health of patients. This study analyses the correlation between gastric cancer-infiltrating immune cell patterns and clinical prognosis and provides a scientific basis for the development of comprehensive tumour prevention and treatment strategies. Method Transcripts and related clinical data from 9-2019 for gastric cancer were downloaded from the TCGA database. The proportions of 22 kinds of immune cells were calculated by CIBERSORT software, and the correlation of each immune cell component ratio with tumour grade, clinical stage and overall survival (OS) was evaluated. Results A total of 413 gene transcript data sets were obtained from the TCGA database, including 381 for gastric cancer and 32 for normal tissues. The expression of various macrophages in tumour tissues was abundant. The immune cell composition, which included resting dendritic cells (p=0.02), M1 macrophages (p=0.031), resting mast cells (p=0.02), CD8 T cells (p=2.445e-04), M0 macrophages (p=6.353e-04), activated mast cells (p=0.006), neutrophils (p=0.003), resting NK cells (p=0.014), and gamma delta T cells (p=0.033), is related to the pathological grade. As the tumour stage of gastric cancer patients progresses, the proportion of some immune cells, including eosinophils (p=0.013), activated mast cells (p=0.042), neutrophils (p=0.007), and resting NK cells (p=0.036) gradually increases, while the proportion of other immune cells, for example, CD8 T cells (p=0.018), Tregs (p=0.039), M1 macrophages (p=0.018), and activated NK cells (p=0.042) gradually decreases. Higher expression of CD8 T cells suggests a better prognosis. Conclusion The composition of tumour-infiltrating immune cells differed greatly in different pathological grades and stages of gastric cancer. CD8 T cells can be used as a prognostic factor for gastric cancer patients.

scholarly journals Comprehensive Analysis of the Immune Microenvironment in Checkpoint Inhibitor Pneumonitis

2022 ◽  
Vol 12 ◽  
Author(s):  
Xinqing Lin ◽  
Jiaxi Deng ◽  
Haiyi Deng ◽  
Yilin Yang ◽  
Ni Sun ◽  
...  
Keyword(s):  
T Cells ◽  
B Cells ◽  
Immune Cells ◽  
Checkpoint Inhibitor ◽  
Memory B Cells ◽  
Gene Set Enrichment Analysis ◽  
Control Group ◽  
Immune Microenvironment ◽  
M1 Macrophages ◽  
Nsclc Patients

BackgroundWhile immune checkpoint inhibitors (ICIs) are a beacon of hope for non-small cell lung cancer (NSCLC) patients, they can also cause adverse events, including checkpoint inhibitor pneumonitis (CIP). Research shows that the inflammatory immune microenvironment plays a vital role in the development of CIP. However, the role of the immune microenvironment (IME) in CIP is still unclear.MethodsWe collected a cohort of NSCLC patients treated with ICIs that included eight individuals with CIP (CIP group) and 29 individuals without CIP (Control group). CIBERSORT and the xCell algorithm were used to evaluate the proportion of immune cells. Gene set enrichment analysis (GSEA) and single-sample GSEA (ssGSEA) were used to evaluate pathway activity. The ridge regression algorithm was used to analyze drug sensitivity.ResultsCIBERSORT showed significantly upregulated memory B cells, CD8+ T cells, and M1 Macrophages in the CIP group. The number of memory resting CD4+ T cells and resting NK cells in the CIP group was also significantly lower than in the Control group. The XCell analysis showed a higher proportion of Class-switched memory B-cells and M1 Macrophages in the CIP group. Pathway analysis showed that the CIP group had high activity in their immune and inflammatory response pathways and low activity in their immune exhaustion related pathway.ConclusionsIn this study, we researched CIP patients who after ICIs treatment developed an inflammatory IME, which is characterized by significantly increased activated immune cells and expression of inflammatory molecules, as well as downregulated immunosuppressive lymphocytes and signaling pathways. The goal was to develop theoretical guidance for clinical guidelines for the treatment of CIP in the future.

scholarly journals Prognostic significance of natural killer cell-associated markers in gastric cancer: quantitative analysis using multiplex immunohistochemistry

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Hee Young Na ◽  
Yujun Park ◽  
Soo Kyung Nam ◽  
Jiwon Koh ◽  
Yoonjin Kwak ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
T Cells ◽  
B Cells ◽  
Nk Cells ◽  
Natural Killer ◽  
Immune Cells ◽  
Nk Cell ◽  
Critical Role ◽  
Killer Cell ◽  
Prognostic Significance

Abstract Background Natural killer (NK) cells mediate the anti-tumoral immune response as an important component of innate immunity. The aim of this study was to investigate the prognostic significance and functional implication of NK cell-associated surface receptors in gastric cancer (GC) by using multiplex immunohistochemistry (mIHC). Methods We performed an mIHC on tissue microarray slides, including 55 GC tissue samples. A total of 11 antibodies including CD57, NKG2A, CD16, HLA-E, CD3, CD20, CD45, CD68, CK, SMA, and ki-67 were used. CD45 + CD3-CD57 + cells were considered as CD57 + NK cells. Results Among CD45 + immune cells, the proportion of CD57 + NK cell was the lowest (3.8%), whereas that of CD57 + and CD57- T cells (65.5%) was the highest, followed by macrophages (25.4%), and B cells (5.3%). CD57 + NK cells constituted 20% of CD45 + CD57 + immune cells while the remaining 80% were CD57 + T cells. The expression of HLA-E in tumor cells correlated with that in tumoral T cells, B cells, and macrophages, but not CD57 + NK cells. The higher density of tumoral CD57 + NK cells and tumoral CD57 + NKG2A + NK cells was associated with inferior survival. Conclusions Although the number of CD57 + NK cells was lower than that of other immune cells, CD57 + NK cells and CD57 + NKG2A + NK cells were significantly associated with poor outcomes, suggesting that NK cell subsets play a critical role in GC progression. NK cells and their inhibitory receptor, NKG2A, may be potential targets in GC.

scholarly journals Prognostic and immunological value of LTB4R in pan-cancer

2021 ◽  
Vol 18 (6) ◽  
pp. 9336-9356
Author(s):  
Sidan Long ◽  
◽  
Shuangshuang Ji ◽  
Kunmin Xiao ◽  
Peng Xue ◽  
...  
Keyword(s):  
Immune Cells ◽  
Prognostic Significance ◽  
Enrichment Analysis ◽  
Negative Influence ◽  
Leukotriene B4 ◽  
Gene Set Enrichment Analysis ◽  
Functional Enrichment ◽  
Immune Infiltration ◽  
Significant Difference ◽  
Pan Cancer

<abstract> <sec><title>Background</title><p>LTB4 receptor 1 (LTB4R), as the high affinity leukotriene B4 receptor, is rapidly revealing its function in malignancies. However, it is still uncertain.</p> </sec> <sec><title>Methods</title><p>We investigated the expression pattern and prognostic significance of LTB4R in pan-cancer across different databases, including ONCOMINE, PrognoScan, GEPIA, and Kaplan-Meier Plotter, in this study. Meanwhile, we explored the significance of LTB4R in tumor metastasis by HCMDB. Then functional enrichment analysis of related genes was performed using GeneMANIA and DAVID. Lastly, utilizing the TIMER datasets, we looked into the links between LTB4R expression and immune infiltration in malignancies.</p> </sec> <sec><title>Results</title><p>In general, tumor tissue displayed higher levels of LTB4R expression than normal tissue. Although LTB4R had a negative influence on pan-cancer, a high expression level of LTB4R was protective of LIHC (liver hepatocellular carcinoma) patients' survival. There was no significant difference in the distribution of LTB4R between non-metastatic and metastatic tumors. Based on Gene Set Enrichment Analysis, LTB4R was implicated in pathways involved in inflammation, immunity, metabolism, and cancer diseases. The correlation between immune cells and LTB4R was found to be distinct across cancer types. Furthermore, markers of infiltrating immune cells, such as Treg, T cell exhaustion and T helper cells, exhibited different LTB4R-related immune infiltration patterns.</p> </sec> <sec><title>Conclusion</title><p>The LTB4R is associated with immune infiltrates and can be used as a prognostic biomarker in pan-cancer.</p> </sec> </abstract>

scholarly journals ILDR1 Is a Prognostic Biomarker and Associated With Immune Infiltration in Gastric Cancer

2021 ◽  
Author(s):  
Yanling Ma ◽  
WenBo Qi ◽  
BaoHong Gu ◽  
XueMei Li ◽  
ZhenYu Yin ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
T Cells ◽  
Dendritic Cells ◽  
Cancer Patients ◽  
Cd8 T Cells ◽  
Immune Cells ◽  
Copy Number ◽  
Sequencing Data ◽  
Number Variation ◽  
Gastric Cancer Patients

Abstract Objective: To investigate the association between ILDR1 and prognosis and immune infiltration in gastric cancer. Methods: We analyzed the RNA sequencing data of 9736 tumor tissues and 8587 normal tissues in the TCGA and GTEx databases through the GEPIA2 platform. The expression of ILDR1 in gastric cancer and normal gastric mucosa tissues with GEPIA and TIMER. Clinical subgroup analysis was made through Kaplan-Meier analysis. Analyzed the correlation between ILDR1 and VEGFA expression in gastric cancer, through the gene sequencing data of gastric cancer in TCGA. Explored the relationship between ILDR1 methylation and the prognosis of gastric cancer patients through the MethSurv database. The correlation between ILDR1 and immune cells and the correlation of copy number variation were explored through the TIMER database. Results: ILDR1-high GC patients had a lower PFS and OS. High ILDR1 expression was significantly correlated with tumor grade. There was a negative correlation between the ILDR1 expression and the abundances of CD8+ T, Macrophages and DC and etc. The methylation level of ILDR1 is associated with a good prognosis of gastric cancer. ILDR1 copy number variation was correlated with immune cells, IDLR1 arm-loss was associated with the infiltration of B cells, CD8+ T cells, CD4+ T cells, macrophages, neutrophils, and dendritic cells, and arm-duplication was associated with the infiltration of B cells, CD8+ T cells, CD4+ T cells, macrophages, neutrophils and dendritic cells. Conclusion: The increased expression of ILDR1 is associated with poor prognosis in patients with gastric cancer. ILDR1 can be used as a novel predictive biomarker to provide a new therapeutic target for gastric cancer patients.

scholarly journals APOC1 is a Potential Prognostic Biomarker and Correlated With Immune Infiltration in ESCC

2020 ◽  
Author(s):  
Jia-yi XIE ◽  
Ming Liu ◽  
Yaxin Luo ◽  
Zhen Wang ◽  
Zhenghong Lu ◽  
...  
Keyword(s):  
T Cells ◽  
Transcription Factors ◽  
Cd8 T Cells ◽  
Immune Cells ◽  
Poor Prognosis ◽  
Killer Cell ◽  
Gene Set Enrichment Analysis ◽  
Immune Infiltration ◽  
Kaplan Meier ◽  
Kaplan Meier Plotter

Abstract PurposeEsophageal cancer (EC) is the sixth leading cause of cancer death worldwide. Esophageal squamous cell carcinoma (ESCC) is a predominant subtype of EC. Identifying diagnostic biomarkers for ESCC is necessary for cancer practice. Increasing evidence illustrates that apolipoprotein C-1 (APOC1) participates in the carcinogenesis. However, the biological function of APOC1 in ESCC remains unclear. Patients and methodsWe investigated the expression level of APOC1 using TIMER2.0 and GEO databases, the prognostic value of APOC1 in ESCC using Kaplan-Meier plotter and TCGA databases. We used LinkedOmics to identify co-expressed genes with APOC1 and perform GO and KEGG pathway analysis. The target networks of kinases, miRNAs and transcription factors were predicted by gene set enrichment analysis (GSEA). The correlations between APOC1 and immune infiltration were calculated using TIMER2.0 and CIBERSORT databases. We further performed the prognostic analysis based on APOC1 expression levels in related immune cells subgroups via Kaplan-Meier plotter database. ResultsAPOC1 was found overexpressed in tumor tissues in multiple ESCC cohorts and high APOC1 expression was related to a dismal prognosis. Multivariate analysis confirmed that APOC1 overexpression was an independent indicator of poor OS. Functional network analysis indicated that APOC1 might regulate the natural killer cell mediated cytotoxicity, phagosome, AMPK and hippo signaling through pathways involving some cancer-related kinases, miRNA and transcription factors. Immune infiltration analysis showed that APOC1 was significantly positively correlated with M0 macrophages cells, M1 macrophages cells and activated NK cells, negatively correlated with regulatory T cells, CD8 T cells, neutrophils and monocytes. High APOC1 expression had a poor prognosis in server immune cells subgroups in ESCC, including decreased CD8+ T cells subgroups. ConclusionThese findings suggest that increased expression of APOC1 is related to poor prognosis and immune infiltration in ESCC. APOC1 holds promise for serving as a valuable diagnostic and prognostic marker in ESCC.

scholarly journals The Functionalities and Clinical Significance of Tumor-Infiltrating Immune Cells in Esophageal Squamous Cell Carcinoma

2021 ◽  
Vol 2021 ◽  
pp. 1-9
Author(s):  
Jishuai Zhang ◽  
Haifeng Wang ◽  
Haitao Wu ◽  
Guangliang Qiang
Keyword(s):  
Gene Expression ◽  
Squamous Cell Carcinoma ◽  
T Cells ◽  
Esophageal Squamous Cell Carcinoma ◽  
Cell Carcinoma ◽  
Natural Killer ◽  
Clinical Significance ◽  
Squamous Cell ◽  
Immune Cells ◽  
Gene Set Enrichment Analysis

Tumor-infiltrating immune cells have been implicated in the tumorigenesis and progression of esophageal squamous cell carcinoma (ESCC). However, the functionalities and clinical significance of immune cells remain largely unveiled. In this study, the gene expression data from the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) were extracted. The relative infiltrating levels were estimated by single-sample gene set enrichment analysis. Some cytotoxic immune cells were attenuated, and resting cytotoxic immune cells were accumulated in ESCC. Remarkably, we also observed that infiltrating levels of macrophage M2 and resting natural killer (NK) cells were increased in nonresponders of CRT, and T cells that had anticancer activities such as activated memory CD4 and T helper 2 (Th2) cells were significantly reduced in ESCC tissues of the nonresponders. Moreover, the high infiltrations of the resting natural killer (NK) and dendritic cell (DC) were observed to result in a shorter overall survival in ESCC. Consistently, high expression of immune checkpoint genes, CTLA4 and HAVCR2, was associated with poor prognosis. Furthermore, STAT5B, a key transcription factor, as well as its target genes, involved in the regulation of T cells, was significantly downregulated in ESCC, especially subgroup I, indicating that downregulation of STAT5B might be associated with reduced T cell-mediated anticancer activity. In conclusion, the present study significantly improved our understanding of the regulatory roles of immune cells in ESCC.

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