Computational Tumor Infiltration Phenotypes Enable the Spatial and Genomic Analysis of Immune Infiltration in Colorectal Cancer.
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ABSTRACT:
SUBMITTER: Failmezger H
PROVIDER: S-EPMC8006941 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:A substantial fraction of patients with stage I-III colorectal adenocarcinoma (CRC) experience disease relapse after surgery with curative intent. However, biomarkers for predicting the likelihood of CRC relapse have not been fully explored. Therefore, we assessed the association between tumor infiltration by a broad array of innate and adaptive immune cell types and CRC relapse risk. We implemented a discovery-validation design including a discovery dataset from Moffitt Cancer Center (MCC; Tampa, FL) and three independent validation datasets: (1) GSE41258 (2) the Molecular Epidemiology of Colorectal Cancer (MECC) study, and (3) GSE39582. Infiltration by 22 immune cell types was inferred from tumor gene expression data, and the association between immune infiltration by each cell type and relapse-free survival was assessed using Cox proportional hazards regression. Within each of the four independent cohorts, CD4+ memory activated T cell (HR: 0.93, 95% CI: 0.90-0.96; FDR = 0.0001) infiltration was associated with longer time to disease relapse, independent of stage, microsatellite instability, and adjuvant therapy. Based on our meta-analysis across the four datasets, 10 innate and adaptive immune cell types associated with disease relapse of which 2 were internally validated using multiplex immunofluorescence. Moreover, immune cell type infiltration was a better predictors of disease relapse than Consensus Molecular Subtype (CMS) and other expression-based biomarkers (Immune-AICMCC:238.1-238.9; CMS-AICMCC: 241.0). These data suggest that transcriptome-derived immune profiles are prognostic indicators of CRC relapse and quantification of both innate and adaptive immune cell types may serve as candidate biomarkers for predicting prognosis and guiding frequency and modality of disease surveillance.
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Project description:BackgroundChronic inflammation is a significant factor in colorectal cancer (CRC) development, especially in colitis-associated CRC (CAC). T-cell exhaustion is known to influence inflammatory bowel disease (IBD) progression and antitumor immunity in IBD patients. This study aimed to identify unique immune infiltration characteristics in CAC patients.MethodsWe studied 20 CAC and 20 sporadic CRC (sCRC) patients, who were matched by tumor stage, grade, and location. Immunohistochemical staining targeted various T-cell markers (CD3, CD4, CD8, and FOXP3), T-cell exhaustion markers (TOX and TIGIT), a B-cell marker (CD20), and a neutrophil marker (CD66b) in tumor and tumor-free mucosa from both groups. The quantification of the tumor immune stroma algorithm assessed immune-infiltrating cells.ResultsCAC patients had significantly lower TOX+ cell infiltration than sCRC in tumors (p = 0.02) and paracancerous tissues (p < 0.01). Right-sided CAC showed increased infiltration of TOX+ cells (p = 0.01), FOXP3+ regulatory T-cells (p < 0.01), and CD20+ B-cells (p < 0.01) compared to left-sided CAC. In sCRC, higher tumor stages (III and IV) had significantly lower TIGIT+ infiltrate than stages I and II. In CAC, high CD3+ (p < 0.01) and CD20+ (p < 0.01) infiltrates correlated with improved overall survival. In sCRC, better survival was associated with decreased TIGIT+ cells (p < 0.038) and reduced CD8+ infiltrates (p = 0.02).ConclusionIn CAC, high CD3+ and CD20+ infiltrates relate to improved survival, while this association is absent in sCRC. The study revealed marked differences in TIGIT and TOX expression, emphasizing distinctions between CAC and sCRC. T-cell exhaustion appears to have a different role in CAC development.
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Project description:The tumor immune microenvironment (TIME) is likely an important determinant of sensitivity to immune checkpoint inhibitor (ICI) treatment. However, a comprehensive analysis covering the complexity and diversity of the TIME and its influence on ICI therapeutic efficacy is still lacking. Data from 782 samples from 10 ICI clinical trials were collected. To infer the infiltration of 22 subsets of immune cells, CIBERSORTx was applied to the bulk tumor transcriptomes. The associations between each cell fraction and the response to ICI treatment, progression-free survival (PFS) and overall survival (OS) were evaluated, modeling cellular proportions as quartiles. Activity of the interferon-γ pathway, the cytolytic activity score and the MHC score were associated with good prognosis in melanoma. Of the immune cells investigated, M1 macrophages, activated memory CD4+ T cells, T follicular helper (Tfh) cells and CD8+ T cells correlated with response and prolonged PFS and OS, while resting memory CD4+ T cells was associated with unfavorable prognosis in melanoma and urothelial cancer. Consensus clustering revealed four immune subgroups with distinct responses to ICI therapy and survival patterns. The cluster with high proportions of infiltrated CD8+ T cells, activated memory CD4+ T cells, and Tfh cells and low levels of resting memory CD4+ T cells exhibited a higher tumor mutation burden and neoantigen load in melanoma and conferred a higher probability of response and improved survival. Local systemic immune cellular differences were associated with outcomes after ICI therapy. Further investigations of the tumor-infiltrating cellular immune response will lay the foundation for achieving durable efficacy.
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Project description:BackgroundThe anti-epidermal growth factor receptor (EGFR) antibody introduces adaptable variations to the transcriptome and triggers tumor immune infiltration, resulting in colorectal cancer (CRC) treatment resistance. We intended to identify genes that play essential roles in cetuximab resistance and tumor immune cell infiltration.MethodsA cetuximab-resistant CACO2 cellular model was established, and its transcriptome variations were detected by microarray. Meanwhile, public data from the Gene Expression Omnibus and The Cancer Genome Atlas (TCGA) database were downloaded. Integrated bioinformatics analysis was applied to detect differentially expressed genes (DEGs) between the cetuximab-resistant and the cetuximab-sensitive groups. Then, we investigated correlations between DEGs and immune cell infiltration. The DEGs from bioinformatics analysis were further validated in vitro and in clinical samples.ResultsWe identified 732 upregulated and 1259 downregulated DEGs in the induced cellular model. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses, along with Gene Set Enrichment Analysis and Gene Set Variation Analysis, indicated the functions of the DEGs. Together with GSE59857 and GSE5841, 12 common DEGs (SATB-2, AKR1B10, ADH1A, ADH1C, MYB, ATP10B, CDX-2, FAR2, EPHB2, SLC26A3, ORP-1, VAV3) were identified and their predictive values of cetuximab treatment were validated in GSE56386. In online Genomics of Drug Sensitivity in Cancer (GDSC) database, nine of twelve DEGs were recognized in the protein-protein (PPI) network. Based on the transcriptome profiles of CRC samples in TCGA and using Tumor Immune Estimation Resource Version 2.0, we bioinformatically determined that SATB-2, ORP-1, MYB, and CDX-2 expressions were associated with intensive infiltration of B cell, CD4+ T cell, CD8+ T cell and macrophage, which was then validated the correlation in clinical samples by immunohistochemistry. We found that SATB-2, ORP-1, MYB, and CDX-2 were downregulated in vitro with cetuximab treatment. Clinically, patients with advanced CRC and high ORP-1 expression exhibited a longer progression-free survival time when they were treated with anti-EGFR therapy than those with low ORP-1 expression.ConclusionsSATB-2, ORP-1, MYB, and CDX-2 were related to cetuximab sensitivity as well as enhanced tumor immune cell infiltration in patients with CRC.
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Project description:The tumor microenvironment (TME) plays a crucial role in tumor progression and metastasis. However, the immune phenotypes of colorectal cancer (CRC) and the underlying immune escape mechanism have not been studied sufficiently. A total of 1802 and 619 CRC samples from the microarray and TCGA cohorts were enrolled, respectively. The ssGSEA algorithm and unsupervised clustering were used for TME cell infiltration speculation and immune phenotype recognition in the above cohorts. A total of 447 samples from Zhongshan Hospital were collected for validation. Immunohistochemistry was performed in this cohort to quantify TME cell infiltration. The single-cell RNA-seq (scRNA-seq) data of 252,940 cells from 60 CRC samples was analyzed for further mechanistic exploration. CRC samples can be classified into three distinct immune phenotypes. Subtype 1, the immune-active subtype, was characterized by high infiltration of activated adaptive immune cells. Subtype 2, the immune-desert subtype, featured high tumor purity and low infiltration of immune and stromal cells. Subtype 3, the stroma-rich subtype, had high infiltration of stromal cells. The stroma-rich subtype conferred a significantly worse prognosis. The three subtypes had different immune escape mechanisms. The immune-active subtype has the highest immune checkpoint expression level. In comparison, the immune-desert subtype had the lowest immunogenicity and defective antigen presentation. The stroma-rich subtype lacked activated immune cells. In conclusion, distinct immune phenotypes and immune escape mechanisms may provide inspiration and direction for further research on CRC immunotherapy.
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Project description:The RNA 5-methylcytosine (m5C) modification has been demonstrated to be an important epigenetic regulator and to impact colorectal cancer (CRC) progression. However, the potential roles of m5C modification in immune cell infiltration in the CRC tumor microenvironment (TME) remain unknown. The m5C modification phenotypes were comprehensively evaluated based on 14 m5C regulators in a meta-CRC cohort of 1792 patients and systematically correlated with the m5C modification phenotypes, immune cell infiltration characteristics and known biological processes. The m5Cscore model was constructed by principal component analysis (PCA) algorithms to quantify the m5C modification phenotypes of individual CRC samples and was used to predict the immunotherapy response. We identified three m5C modification phenotypes associated with distinct clinical outcomes and biological processes among the 1792 meta-CRC patients. Three phenotypes with a highly consistent TME landscape and characteristics were revealed: immune excluded, immune desert and immune inflammation. The meta-CRC patients were divided into high and low m5Cscore subgroups based on the m5Cscore. The m5Cscore was confirmed to have a negative correlation with infiltrating immune cells and PD-L1 expression and a positive correlation with tumor mutation burden (TMB), mutation rate and microsatellite instability (MSI) score. Moreover, patients in the low m5Cscore group had better immunotherapy responses and significant durable survival benefits in independent anti-PD-1/L1 immunotherapy cohorts for the immune checkpoint inhibitor (ICI) therapeutic strategy. This study revealed that m5C modification plays a crucial role in TME composition and complexity. Comprehensive evaluation of the m5C modification phenotypes of individual patients will enhance our understanding of TME characteristics and promote the application of more appropriate and personalized treatment strategies.
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Project description:Studies have shown that LIM domain kinase 1 (LIMK1) is upregulated in a variety of tumors and may be a potential detection target. The present study analyzed the expression difference of LIMK1 and its relationship with tumor clinicopathological characteristics and tumor microenvironment in colorectal cancer (CRC). The transcriptomic data of LIMK1 with CRC were downloaded from The Cancer Genome Atlas (TCGA) database and GEO databases for analyzing the expression of LIMK1 mRNA and the correlation with the prognosis of patients. The protein expression of LIMK1 was obtained from the Human Protein Atlas. The receiver operating characteristic (ROC) curve and Kaplan-Meier was used to evaluate the expression characteristics and prognostic differences of LIMK1 in CRC. STRING was used to analyze co-expression genes of LIMK1. The tumor immune estimation resource was applied to the correlation between LIMK1 expression and immune infiltrates. The present study verified LIMK1 expression at the level of clinical samples collected from the Tianjin Medical University General Hospital and cell lines using reverse transcription-quantitative PCR. The mRNA and protein expression of LIMK1 were both upregulated in tumor tissues compared with adjacent tissues in CRC. The expression levels of LIMK1 were positively associated with clinical-pathological features of CRC including lymphatic invasion (P=4.00×10−2) and high pathologic stages (P=4.20×10−2). The AUC value of LIMK1 in CRC was 0.937 (95% CI: 0.918-0.957) through ROC analysis. Under the best cut-off value (4.009), the sensitivity and specificity were 98 and 81.9%. LIMK1 expression was mainly related to CD4+ T cells, macrophages and dendritic cells in the immune microenvironment of CRC. In conclusion, the high expression of LIMK1 in CRC was closely related to the clinical features and prognosis of patients. Therefore, LIMK1 was a promising prognostic indicator and a potential target for immunotherapy in CRC.
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Project description:BackgroundBladder cancer (BC) is the sixth most common cancer and the ninth leading cause of cancer death among men in the world. Previous studies have shown that tumor hypoxia plays an important role in the occurrence and development of BC, but the role of tumor hypoxia in the prognosis and immune infiltration of BC remains unclear. Our aim was to perform a bioinformatics analysis combined with a clinical analysis to explore the roles of hypoxia in BC.MethodsWe acquired datasets (GSE13507, GSE5287, and GSE1827) containing mRNA expression information from BC cohorts from the Gene Expression Omnibus (GEO) and measured the Hypoxia score using the Gene Set Variation Analysis (GSVA). Then we used X-tile method and log-rank test and Pearson's correlation test to analyze the relation among the Hypoxia score and the clinicopathological and immunological characteristics of BC and used stepwise Cox regression analysis to establish a Prognostic model.ResultsHypoxia was found to be closely associated with tumor grade, pathological type, invasion, and prognosis of BC in our study. Moreover, we determined that hypoxia was closely related to the infiltration abundance of multiple immune cells through a correlation analysis, and the tumor immune cell infiltration was further found to be significantly associated with the tumor grade and tumor type of BC. Furthermore, we constructed several models based on the Hypoxia score and tumor immune infiltration with C-indexes ranging from 0.703 and 0.888, which showed good performance in predicting the prognosis of BC.ConclusionsOur study showed that hypoxia plays an important role in the progression, prognosis, and tumor immune infiltration of BC. Our models based on hypoxia and tumor immune infiltration play a guiding role in the prognosis and treatment of BC patients.
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Project description:OBJECTIVES:Analysis of tumor immune infiltration has been suggested to outperform tumor, node, metastasis staging in predicting clinical course of colorectal cancer (CRC). Infiltration by cells expressing OX40, a member of the tumor necrosis factor receptor family, or CD16, expressed by natural killer cells, monocytes, and dendritic cells, has been associated with favorable prognosis in patients with CRC. We hypothesized that assessment of CRC infiltration by both OX40+ and CD16+ cells might result in enhanced prognostic significance. METHODS:Colorectal cancer infiltration by OX40 and CD16 expressing cells was investigated in 441 primary CRCs using tissue microarrays and specific antibodies, by immunohistochemistry. Patients' survival was evaluated by Kaplan-Meier and log-rank tests. Multivariate Cox regression analysis, hazard ratios, and 95% confidence intervals were also used to evaluate prognostic significance of OX40+ and CD16+ cell infiltration. RESULTS:Colorectal cancer infiltration by OX40+ and CD16+ cells was subclassified into 4 groups with high or low infiltration levels in all possible combinations. High levels of infiltration by both OX40+ and CD16+ cells were associated with lower pT stage, absence of peritumoral lymphocytic (PTL) inflammation, and a positive prognostic impact. Patients bearing tumors with high infiltration by CD16+ and OX40+ cells were also characterized by significantly longer overall survival, as compared with the other groups. These results were confirmed by analyzing an independent validation cohort. CONCLUSIONS:Combined infiltration by OX40+ and CD16+ immune cells is an independent favorable prognostic marker in CRC. The prognostic value of CD16+ immune cell infiltration is significantly improved by the combined analysis with OX40+ cell infiltration.
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