Effects of Hypoxia in Intestinal Tumors on Immune Cell Behavior in the Tumor Microenvironment.

Luping Zhang,Hong Xu,Shaokun Wang,Yachen Wang,Nan Zhang,Weidan Zhao,Yingli Zhang

doi:10.3389/fimmu.2021.645320

Luping Zhang, Hong Xu + Show 5 more

Open Access

https://doi.org/10.3389/fimmu.2021.645320

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Abstract

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.

Highlights

Since Stephen Paget proposed the “seed and soil” theory of cancer development and tumor metastasis [1], the understanding of the tumor microenvironment has gradually deepened
The gene symbol set was obtained from the Gene Set Enrichment Analysis (GSEA) website, which provides the names of all hypoxia-related genes
We extracted the data on hypoxiarelated gene expression and screened genes associated with prognosis using univariate Cox regression analysis (Figure 1C)

Summary

Introduction

Since Stephen Paget proposed the “seed and soil” theory of cancer development and tumor metastasis [1], the understanding of the tumor microenvironment has gradually deepened. An imbalance between nutrient supply and demand within the tumor often leads to hypoxia, glucose deficiency, and an acidic tumor microenvironment [4]. Tumor cells can use immune escape mechanisms to drive metastasis and invasion in anoxic environments [5]. This has increased research interest into the relationship between hypoxia and the tumor immune microenvironment. 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. The functional relationship between hypoxia and the tumor microenvironment remains unclear. We aimed to investigate the effect of hypoxia on the intestinal tumor microenvironment

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