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Prognostic value of immune scores in the microenvironment of colorectal cancer.

ABSTRACT: Cancer immunotherapy has become an important means of cancer treatment; however, the complex composition and heterogeneity of the colorectal cancer (CRC) microenvironment pose a huge challenge to cancer immunotherapy. Using data downloaded from The Cancer Genome Atlas database, the differences in the microenvironment between cases with low and high immune scores were examined at the multiomics level using bioinformatics approaches. It was revealed that the samples with high immune scores had good cytolytic immune responses and relatively abundant stromal cells, as well as significant infiltration of 22 immune cell subsets and a high non-synonymous mutation burden and neoantigen burden. All of these characteristics contribute to a good prognosis. To better understand the impact of immune-related genes on prognosis, differentially expressed genes between the low and high immune score samples were identified and it was concluded that serpin family Emember 1 (SERPINE1) and ubiquitin C-terminal hydrolase L1 (UCHL1) may be potential therapeutic targets. The relationship between the immune score and the infiltration of 22 immune cells and the difference in SERPINE1 expression were verified by analyzing the GSE17536 and GSE21510 data sets downloaded from the Gene Expression Omnibus database. The present study analyzed the unique properties of immune cells in the CRC microenvironment, which are of great significance for understanding CRC immune mechanism and may also provide novel ideas for the targeted design of cancer immunotherapy.

SUBMITTER: Yuan W

PROVIDER: S-EPMC7509622 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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Prognostic value of immune scores in the microenvironment of colorectal cancer.

Yuan Wenliang W Cai Wei W Huang Xiao X Peng Sihua S

Oncology letters 20200918 5

Cancer immunotherapy has become an important means of cancer treatment; however, the complex composition and heterogeneity of the colorectal cancer (CRC) microenvironment pose a huge challenge to cancer immunotherapy. Using data downloaded from The Cancer Genome Atlas database, the differences in the microenvironment between cases with low and high immune scores were examined at the multiomics level using bioinformatics approaches. It was revealed that the samples with high immune scores had goo ...[more]

PMID: 32994819

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Project description:BACKGROUND:Colon cancer is a disease with high malignancy and incidence in the world. Tumor immune microenvironment (TIM) and tumor mutational burden (TMB) have been proved to play crucial roles in predicting clinical outcomes and therapeutic efficacy, but the correlation between them and the underlying mechanism were not completely understood in colon cancer. METHODS:In this study, we used Single-Sample Gene Set Enrichment Analysis (ssGSEA) and unsupervised consensus clustering analysis to divide patients from the TCGA cohort into three immune subgroups. Then we validated their differences in immune cell infiltration, overall survival outcomes, clinical phenotypes and expression levels of HLA and checkpoint genes by Mann-Whitney tests. We performed weighted correlation network analysis (WGCNA) to obtain immunity-related module and hub genes. Then we explored the underlying mechanism of hub genes by gene set enrichment analysis (GSEA) and gene set evaluation analysis (GSVA). Finally, we gave an overall view of gene variants and verified the correlation between TIM and TMB by comparing microsatellite instability (MSI) and gene mutations among three immune subgroups. RESULTS:The colon cancer patients were clustered into low immunity, median immunity and high immunity groups. The median immunity group had a favorable survival probability compared with that of the low and high immunity groups. Three groups had significant differences in immune cell infiltration, tumor stage, living state and T classification. We got 8 hub genes (CCDC69, CLMP, FAM110B, FAM129A, GUCY1B3, PALLD, PLEKHO1 and STY11) and predicted that immunity may correlated with inflammatory response, KRAS signaling pathway and T cell infiltration. With higher immunity, the TMB was higher. The most frequent mutations in low and median immunity groups were APC, TP53 and KRAS, while TTN and MUC16 showed higher mutational frequency in high immunity group. CONCLUSIONS:We performed a comprehensive evaluation of the immune microenvironment landscape of colon cancer and demonstrated the positive correlation between immunity and TMB. The hub genes and frequently mutated genes were strongly related to immunity and may give suggestion for immunotherapy in the future.

Project description:IntroductionCancer progression is determined not only by the malignant behavior of tumors but also by the immune microenvironment. The tumor immune microenvironment also plays a pivotal role in determining the clinical response of non-small-cell lung cancer (NSCLC) to immunotherapies. To understand the possible mechanisms and explore new targets in lung cancer immunotherapy, we characterized the immune profiles in NSCLC patients.MethodsSeventy-one NSCLC patients who underwent radical resection were selected. The immune cell composition in paired tumor and adjacent normal lung tissues was tested by flow cytometry. The associations of tumor immune microenvironment characteristics with clinicopathological factors and overall survival were analyzed. Kaplan-Meier curves and Cox proportional hazards models were used to determine differences in survival.ResultsCompared with adjacent normal lung tissues, an increased proportion of CD45+ hematopoietic-derived cells, CD4+ T cell subtypes, Tregs and B cells was observed in tumor samples with a reduced frequency of myeloid cell populations. There was no significant increase in total CD8+ T cells, but both PD1+ and CD38+ CD8+ T cells were significantly enriched in tumor samples and statistically significantly associated with tumor size. In addition, positive CD38 expression was highly correlated with PD1 positivity. A high proportion of CD8+ T cells and a low percentage of PD1+ CD8+ T cells were statistically significantly associated with better survival in stage II and III patients, whereas a low frequency of CD38+ CD8+ T cells was statistically significantly associated with better survival in all patients and identified as an independent prognostic factor (p=0.049).ConclusionWe profiled the immune cells in the tumor tissues of NSCLC patients using flow cytometry. The results revealed significant enrichment of infiltrating immune cells. A strong correlation was identified between CD38 and PD-1 expression on CD8+ T cells in tumors. CD8+ T cells and their subtypes play a critical role in the prediction of prognosis.

Project description:BackgroundBreast cancer is one of the most frequently diagnosed cancers among women worldwide. Alterations in the tumor microenvironment (TME) have been increasingly recognized as key in the development and progression of breast cancer in recent years. To deeply comprehend the gene expression profiling of the TME and identify immunological targets, as well as determine the relationship between gene expression and different prognoses is highly critical.MethodsThe stromal/immune scores of breast cancer patients from The Cancer Genome Atlas (TCGA) were employed to comprehensively evaluate the TME. Then, TME characteristics were assessed, overlapping genes of the top 3 Gene Ontology (GO) terms and upregulated differentially expressed genes (DEGs) were analyzed. Finally, through combined analyses of overall survival, time-dependent receiver operating characteristic (ROC), and protein-protein interaction (PPI) network, novel immune related genes with good prognosis were screened and validated in both TCGA and GEO database.ResultsAlthough the TME did not correlate with the stages of breast cancer, it was closely associated with the subtypes of breast cancer and gene mutations (CDH1, TP53 and PTEN), and had immunological characteristics. Based on GO functional enrichment analysis, the upregulated genes from the high vs low immune score groups were mainly involved in T cell activation, the external side of the plasma membrane, and receptor ligand activity. The top GO terms of the upregulated DEGs from the high vs low immune score groups exhibited better prognosis in breast cancer; 15 of them were related to good prognosis in breast cancer, especially CD226 and KLRC4-KLRK1.ConclusionsHigh CD226 and KLRC4-KLRK1 expression levels were identified and validated to correlate with better overall survival in specific stages or subtypes of breast cancer. CD226, KLRC4-KLRK1 and other new targets seem to be promising avenues for promoting antitumor targeted immunotherapy in breast cancer.

Project description:Colorectal cancer (CRC) ranks as the second leading cause of cancer-related mortality globally and is the third most prevalent cancer. The effective treatment of CRC is challenged by tumor drug resistance, underscoring the urgent need for novel therapeutic strategies. It is well recognized that epigenetic modifications, particularly DNA methylation, significantly contribute to the initiation and advancement of CRC. Tumors frequently exhibit hypermethylation of specific gene promoters alongside a general hypomethylation of genomic DNA. In normal tissues, gene promoters, particularly those of tumor suppressor genes, are typically unmethylated, whereas they are often hypermethylated in cancerous tissues. Previous studies have identified the methylation status of the CpG island within the SLC30A10 gene as a reliable biomarker for CRC. Notably, a hypermethylated phenotype is inversely correlated with SLC30A10 expression. However, the precise functional implications of SLC30A10 suppression in the context of CRC progression remain to be elucidated.). The investigation of molecular pathways involved in metal metabolism in CRC has not been conducted previously at the transcriptomic level. Furthermore, the relationship between the mutational characteristics of tumors—such as individual mutations, mutational burden, and microsatellite instability—and the activity of genes related to metal metabolic pathways has not been explored. This project aims to be the first to examine the antitumor potential of modulating the transport systems for manganese and zinc ions in CRC. The molecular function of SLC30A10 is to export zinc (Zn) and manganese (Mn) ions from the cell. Additionally, SLC30A10 plays a crucial role in mitigating Mn-induced cytotoxicity and facilitates Zn transport to early endosomes while promoting endosomal recirculation to avert Zn toxicity. Our findings indicate that overexpression of SLC30A10 is correlated with the knockout of its functional antagonist, SLC39A14 in the HuTu80 and HCT-15 cell lines.

Project description:Esophageal cancer is the eighth most common cancer and the sixth leading cause of cancer death worldwide. Hence, for a better understanding of tumor microenvironment and to seek for novel molecular targets for esophageal cancer, we performed related studies on two histopathological subtypes of esophageal cancer: esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC). Bioinformatic analyses were conducted based on the RNA-seq, genomic mutation, and clinical data from TCGA and GEO cohorts. We clustered patients into high-immunity and low-immunity groups through the ssGSEA results. The ESTIMATE algorithm was used to evaluate the tumor microenvironment. Patients with high immunity in both ESCC and EAC had lower tumor purity and poor survival. Subsequently, CIBERSORT was performed to learn about the detailed difference of tumor-infiltrating lymphocytes (TILs) between high- and low-immunity patients. Specific increase of M2 macrophages and decrease of activated dendric cells can be observed in ESCC and EAC, respectively. The most enriched functions and pathways of high-immunity patients were immunoglobulin complex, MHC class II protein complex, and allograft rejection according to the GO terms and KEGG. Two prognostic immune-related multi-lncRNA risk models were constructed and validated by ROC curve and PCA in ESCC and EAC. High-risk patients in both subtypes had poor survival, advanced clinical characteristics, and higher drug susceptibility except cisplatin and sorafenib. In addition, the tumor mutation burden (TMB) was positively correlated with the risk level in the ESCC and EAC and showed distinct differences between the two subtypes. In summary, we comprehensively analyzed the tumor microenvironment for two subtypes of esophageal cancer, identified two multi-lncRNA signatures predictive for the prognosis, and explored the possibility of the signatures to forecast drug susceptibility as well as TMB for the first time. The findings may serve as a conceptual basis for innovative strategy of individualized immunotherapy for esophageal cancer.

Project description:Breast cancer is one of the most common malignancies in women worldwide. Many studies have shown that tumor microenvironment cells, immune cells, and stromal cell infiltration have an important impact on prognosis, so it is important to identify biomarkers for achieving better treatment and prognosis.To better understand the relationship between immune and stromal cell-related genes and prognosis, we screened patients with breast cancer in The Cancer Genome Atlas (TCGA) database and divided them into high and low groups based on immune/stromal scores. We next identified differentially expressed immune-related genes that are significantly associated with the prognosis of patients with breast cancer for functional enrichment analysis and protein-protein interaction networks, respectively. Finally, we selected a separate breast cancer cohort in gene expression synthesis (GEO) for validation.Both immune scores and stromal scores are meaningful in the correlation of subtype classification. Disease-free survival of cases with the high score group of immune scores is statistically longer than the cases in the low score group. Differentially expressed immune-related genes extracted from the comparison can effectively evaluate the prognosis of patients with breast cancer and these genes are primarily involved in immune responses, extracellular matrix, and chemokine activity. At last, we obtained a series of verified tumor immune-related genes that predict the prognosis of patients with breast cancer.Combining the Estimation of Stromal and Immune Cells in Malignant Tumor Tissues using Expression database and the TCGA database to extract the list of tumor microenvironment related genes which may help to outline the prognosis of patients with breast cancer. Some previously overlooked genes have the potential to become additional biomarkers for breast cancer. Further research on these genes can reveal a new understanding of the potential relationship between tumor microenvironment and breast cancer prognosis.

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Prognostic value of immune scores in the microenvironment of colorectal cancer.

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Prognostic value of immune scores in the microenvironment of colorectal cancer.

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