Immune cell profiles in the tumor microenvironment of early-onset, intermediate-onset, and later-onset colorectal cancer

Author(s):  
Tomotaka Ugai ◽  
Juha P. Väyrynen ◽  
Mai Chan Lau ◽  
Jennifer Borowsky ◽  
Naohiko Akimoto ◽  
...  
2021 ◽  
Author(s):  
Wenhui Zhong ◽  
Feng Zhang ◽  
Xin Lu ◽  
Kaijun Huang ◽  
Junming Bi ◽  
...  

Abstract Background: Tumor-infiltrating immune cells (TIIC) are the major components of the tumor microenvironment (TME) and play vital roles in the tumorigenesis and progression of colorectal cancer (CRC). Increasing evidence has elucidated their significances in predicting prognosis and therapeutic efficacy. Nonetheless, the immune infiltrative landscape of CRC remains largely unknown. Methods: All the RNA-seq transcriptome data and full clinical annotation of 1213 colorectal cancer patients were downloaded from The Cancer Genome Atlas (TCGA) and Gene-Expression Omnibus (GEO) database. The “CIBERSORT” and “estimate” R package were applied to calculate 22 infiltrated immune cell fractions and stromal and immune score. Three TIIC patterns were determined by Unsupervised clustering methods. Through using principal-component analysis, TIIC scores were established. Data for potential agents comes from the Profiling Relative Inhibition Simultaneously in Mixtures (PRISM) and Cancer Therapeutics Response Portal database (CTRP). Results:In this study, we identified three distinct TIIC patterns characterized by distinct immunological features in 1213 CRC samples from multiple platforms. Base on the TIIC-related gene signatures from three clusters, we constructed a scoring system to quantify the immune infiltration level of individual samples in the CRC cohort and the clinical benefits of different groups. The high TIIC score group was marked by increased immune activation status and favorable prognosis. Conversely, low TIIC score group was featured with immune-desert phenotype and poor prognosis, along with the activation of transforming growth factor-β (TGF-β), WNT, ECM receptor interaction, and VEGF signaling pathways. Meanwhile, the high TIIC score group was also correlated with enhanced efficacy of immunotherapy. Additional, four chemotherapy drugs, seven CTRP-derived drug compounds and six PRISM-derived drug compounds were identified as potential drug for CRC among high and low TIIC subgroups.Conclusions: Collectively, as an effective prognostic biomarker and predictive indicator, the TIIC score plays an important role in the evaluation of CRC prognosis and the response of immunotherapy. Investigation of the TIIC patterns might provide us a promising target for improving immunotherapeutic efficacy in CRC.


2020 ◽  
Author(s):  
Luping Zhang ◽  
Shaokun Wang ◽  
Yachen Wang ◽  
Weidan Zhao ◽  
Yingli Zhang ◽  
...  

Abstract Background: Imbalanced nutritional supply and demand in the tumor microenvironment often leads to hypoxia. The subtle interaction between hypoxia and immune cell behavior plays an important role in tumor occurrence and development. However, the functional relationship between hypoxia and the tumor microenvironment remains unclear. Therefore, we aimed to investigate the effect of hypoxia on the intestinal tumor microenvironment.Method: We extracted the names of hypoxia-related genes from the Gene Set Enrichment Analysis (GSEA) database and screened them for those associated with the prognosis of colorectal cancer, with the final list including ALDOB, GPC1, ALDOC, and SLC2A3. Using the sum of the expression levels of these four genes, provided by The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases, and the expression coefficients, we developed a hypoxia risk score model. Using the median risk score value, we divided the patients in the two databases into high- and low-risk groups.GSEA was used to compare the enrichment differences between the two groups.We used the CIBERSORT computational method to analyze immune cell infiltration.Finally,the correlation between these five genes and hypoxia was analyzed. Result: The prognosis of the two groups differed significantly, with a higher survival rate in the low-risk group than in the high-risk group.We found that the different risk groups were enriched by immune-related and inflammatory pathways. We identified activated CD4 memory T cells and M0 macrophages in TCGA and GEO databases and found that CCL2/4/5, CSF1, and CX3CL1 contributed toward the increased infiltration rate of these immune cell types. Finally, we observed a positive correlation between the five candidate genes’ expression and the risk of hypoxia, with significant differences in the level of expression of each of these genes between patient risk groups.Conclusion: Overall, our data suggest that hypoxia is associated with the prognosis and rate of immune system infiltration in patients with colorectal cancer. This finding may improve immunotherapy for colorectal cancer.


2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 3519-3519
Author(s):  
Ning Jin ◽  
Xiaokui Mo ◽  
Rebecca Hoyd ◽  
Ayse Selen Yilmaz ◽  
YunZhou Liu ◽  
...  

3519 Background: The incidence of colorectal cancer (CRC) in young adults ( < 50 years old) has been rapidly increasing by 2% per year since early 1990. Approximately 20% of early-onset (EO) CRC cases are due to germline gene mutations. However, the etiology of sporadic EO CRC remains poorly understood. Research suggests that environmental factors such as the Western diet (high in fat and low in fiber) may be associated with an increased incidence of sporadic EO CRC. The gut microbiota decompose and ferment dietary fibers to produce microbial metabolites, which play pivotal roles in maintaining the integrity of intestinal epithelium as well as the immune cell homeostasis. Also, these microbial metabolites may influence the host epigenome by altering either the activity of epigenetic enzymes or by modifying the availability of cofactors needed for epigenetic modifications. The aim of our research is to associate intratumoral microbiota with methylation pattern and immune cell composition in EO CRC. Methods: A total of 358 CRC cases, including 54 cases of EO CRC (age < 50 years) and 304 cases of late onset (LO) CRC (age ≥ 50 years), with matched methylation array (Infinium HM450), RNA-sequencing (Illumina HiSeq) from colon adenocarcinomas (COAD) and rectal adenocarcinomas (READ), and clinicopathological information of each patient, were extracted from the Cancer Genome Atlas (TCGA). We characterized and compared the intra-tumoral microbiota composition, tumor-infiltrating lymphocytes (TILs), and methylation profile between EO and LO CRC. Results: We found that there is a distinct microbial distribution, gene expression and methylation pattern in the EO CRC when compared with LO CRC. Non-human sequences from several kingdoms including bacteria, fungi and viruses were found and the incidences were consistent with reported values by other methods, e.g. Fusobacterium incidence. The EO CRC cases showed global hypomethylation, even though hypermethylation pattern is expected in the young chronological age group (known as Horvath’s clock). Pathway overrepresentation analysis of differentially expressed genes showed significant activation of p53 and pentose phosphate pathways and de novo nucleotide synthesis in EO CRC. Integration across datasets showed positive correlations between microbes and inflammasome pathway, positive correlation with regulatory T cells (Tregs), and negative correlations with CD4 memory T cells. Conclusions: These data suggest a mechanism by which the colorectal cancer-associated microbiota may be associated with epigenetic regulation and host immune response.


Cancers ◽  
2019 ◽  
Vol 11 (12) ◽  
pp. 1994 ◽  
Author(s):  
Hibah Shaath ◽  
Salman Toor ◽  
Varun Sasidharan Nair ◽  
Eyad Elkord ◽  
Nehad M. Alajez

Colorectal cancer (CRC) is among the leading causes of cancer-related deaths worldwide, underscoring a need for better understanding of the disease and development of novel diagnostic biomarkers and therapeutic interventions. Herein, we performed transcriptome analyses on peripheral blood mononuclear cells (PBMCs), CRC tumor tissue and adjacent normal tissue from 10 CRC patients and PBMCs from 15 healthy controls. Up regulated transcripts from CRC PBMCs were associated with functions related to immune cell trafficking and cellular movement, while downregulated transcripts were enriched in cellular processes related to cell death. Most affected signaling networks were those involved in tumor necrosis factor (TNF) and interleukin signaling. The expression of selected immune-related genes from the RNA-Seq data were further validated using qRT-PCR. Transcriptome analysis of CRC tumors and ingenuity pathway analysis revealed enrichment in several functional categories related to cellular movement, cell growth and proliferation, DNA replication, recombination and repair, while functional categories related to cell death were suppressed. Upstream regulator analysis revealed activation of ERBB2 and FOXM1 networks. Interestingly, there were 18 common upregulated and 36 common downregulated genes when comparing PBMCs and tumor tissue, suggesting transcriptomic changes in the tumor microenvironment could be reflected, in part, in the periphery with potential utilization as disease biomarkers.


2021 ◽  
Author(s):  
Yi Liu ◽  
Long Cheng ◽  
Chao Li ◽  
Chen Zhang ◽  
Wang Lei ◽  
...  

Abstract Colorectal cancer (CRC) ranks fourth among the deadliest cancers globally, and the progression is highly affected by the tumor microenvironment (TME). This study explores the relationship between TME and colorectal cancer prognosis and identifies prognostic genes related to the CRC microenvironment. We collected the gene expression data from The Cancer Genome Atlas (TCGA) and calculated the scores of stromal/immune cells and their relations to clinical outcomes in colorectal cancer by the ESTIMATE algorithm. Lower immune scores were significantly related to malignant progression of CRC (stage, p=0.014; metastasis, p=0.001). We screened 292 differentially expressed genes (DEGs) by dividing CRC cases into high and low stromal/immune score groups. Functional enrichment analyses and protein-protein interaction (PPI) networks illustrated that these DEGs were closely involved in immune response, cytokine-cytokine receptor interaction, and chemokine signaling pathway. Six DEGs (FABP4, MEOX2, MMP12, ERMN, TNFAIP6, and CHST11) with prognostic value were identified by survival analysis and validated in an independent cohort (GSE17386). The six DEGs were significantly related to immune cell infiltration levels based on the Tumor Immune Estimation Resource (TIMER). The results might contribute to discovering new diagnostic and prognostic biomarkers and new treatment targets for colorectal cancer.


2021 ◽  
Vol 12 ◽  
Author(s):  
Luping Zhang ◽  
Shaokun Wang ◽  
Yachen Wang ◽  
Weidan Zhao ◽  
Yingli Zhang ◽  
...  

BackgroundImbalanced nutritional supply and demand in the tumor microenvironment often leads to hypoxia. The subtle interaction between hypoxia and immune cell behavior plays an important role in tumor occurrence and development. However, the functional relationship between hypoxia and the tumor microenvironment remains unclear. Therefore, we aimed to investigate the effect of hypoxia on the intestinal tumor microenvironment.MethodWe extracted the names of hypoxia-related genes from the Gene Set Enrichment Analysis (GSEA) database and screened them for those associated with colorectal cancer prognosis, with the final list including ALDOB, GPC1, ALDOC, and SLC2A3. Using the sum of the expression levels of these four genes, provided by The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases, and the expression coefficients, we developed a hypoxia risk score model. Using the median risk score value, we divided the patients in the two databases into high- and low-risk groups. GSEA was used to compare the enrichment differences between the two groups. We used the CIBERSORT computational method to analyze immune cell infiltration. Finally, the correlation between these five genes and hypoxia was analyzed.ResultThe prognosis of the two groups differed significantly, with a higher survival rate in the low-risk group than in the high-risk group. We found that the different risk groups were enriched by immune-related and inflammatory pathways. We identified activated M0 macrophages in TCGA and GEO databases and found that CCL2/4/5, and CSF1 contributed toward the increased infiltration rate of this immune cell type. Finally, we observed a positive correlation between the five candidate genes’ expression and the risk of hypoxia, with significant differences in the level of expression of each of these genes between patient risk groups.ConclusionOverall, our data suggest that hypoxia is associated with the prognosis and rate of immune cell infiltration in patients with colorectal cancer. This finding may improve immunotherapy for colorectal cancer.


2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e15236-e15236
Author(s):  
Peng Luo ◽  
Anqi Lin ◽  
Jian Zhang

e15236 Background: In recent years, cancer immunotherapy has been extensively studied, and colorectal cancer (CRC) patients have also derived clinical benefits from immunotherapy, especially CRC patients with mismatch repair deficiency (dMMR)/microsatellite instability-high (MSI-H), whose sensitivity to immune checkpoint inhibitors (ICIs) is significantly higher than that of patients with microsatellite-stable (MSS)/microsatellite instability-low (MSI-L) disease. This study suggests that patients with MSI-H CRC have a higher mutational burden and more immune cell infiltration than those with MSS/MSI-L disease. However, most studies have not systematically evaluated the immune characteristics and immune microenvironments of MSI-H and MSS/MSI-L CRC. Methods: A published CRC cohort with mutation and immunotherapy-related prognostic data was collected. We analyzed the relationship between the MSI status and prognosis of ICI treatment in an immunotherapy cohort. We then further used mutation data for the immunotherapy and The Cancer Genome Atlas (TCGA)-CRC (colon adenocarcinoma (COAD) + rectum adenocarcinoma (READ) cohorts. For mRNA expression, mutation data analysis of the immune microenvironment and immunogenicity under different MSI status was performed. Results: Compared with MSS/MSI-L CRC patients, patients with MSI-H CRC significantly benefited from ICI treatment. We found that MSI-H CRC had more immune cell infiltration, higher expression of immune-related genes and higher immunogenicity than MSS/MSI-L disease. The MANTIS score used to predict the MSI status was positively correlated with immune cells, immune-related genes, and immunogenicity. In addition, subtype analysis showed that COAD and READ might have different tumor immune microenvironments. Conclusions: MSI-H CRC may have an inflammatory tumor microenvironment and increased sensitivity to ICIs. Unlike those of MSI-H READ, the immune characteristics of MSI-H COAD may be consistent with those of MSI-H CRC. Furthermore, the possible mechanism underlying the prognostic differences among CRC patients receiving ICIs in relation to the immune microenvironment were elucidated to provide theoretical guidance for further improving the curative effect of ICIs treatment on MSI-H CRC patients in the future and solve the problems underlying why MSS/MSI-L CRC patients do not benefit from ICIs treatment.


2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Yi Liu ◽  
Long Cheng ◽  
Chao Li ◽  
Chen Zhang ◽  
Lei Wang ◽  
...  

AbstractColorectal cancer (CRC) ranks fourth among the deadliest cancers globally, and the progression is highly affected by the tumor microenvironment (TME). This study explores the relationship between TME and colorectal cancer prognosis and identifies prognostic genes related to the CRC microenvironment. We collected the gene expression data from The Cancer Genome Atlas (TCGA) and calculated the scores of stromal/immune cells and their relations to clinical outcomes in colorectal cancer by the ESTIMATE algorithm. Lower immune scores were significantly related to the malignant progression of CRC (metastasis, p = 0.001). We screened 292 differentially expressed genes (DEGs) by dividing CRC cases into high and low stromal/immune score groups. Functional enrichment analyses and protein–protein interaction (PPI) networks illustrated that these DEGs were closely involved in immune response, cytokine–cytokine receptor interaction, and chemokine signaling pathway. Six DEGs (FABP4, MEOX2, MMP12, ERMN, TNFAIP6, and CHST11) with prognostic value were identified by survival analysis and validated in two independent cohorts (GSE17538 and GSE161158). The six DEGs were significantly related to immune cell infiltration levels based on the Tumor Immune Estimation Resource (TIMER). The results might contribute to discovering new diagnostic and prognostic biomarkers and new treatment targets for colorectal cancer.


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