Screening and Validation of the Hypoxia-Related Signature of Evaluating Tumor Immune Microenvironment and Predicting Prognosis in Gastric Cancer

Abstract

BackgroundHypoxia is one driving factor of gastric cancer. It causes a series of immunosuppressive processes and malignant cell responses, leading to a poor prognosis. It is clinically important to identify the molecular markers related to hypoxia.MethodsWe screened the prognostic markers related to hypoxia in The Cancer Genome Atlas database, and a risk score model was developed based on these markers. The relationships between the risk score and tumor immune microenvironment were investigated. An independent validation cohort from Gene Expression Omnibus was applied to validate the results. A nomogram of risk score model and clinicopathological factor was developed to individually predict the prognosis.ResultsWe developed a hypoxia risk score model based on SERPINE1 and EFNA3. Quantified real-time PCR was further applied to verified gene expressions of SERPINE1 and EFNA3 in gastric cancer patients and cell lines. A high-risk score is associated with a poor prognosis through the immunosuppressive microenvironment and immune escape mechanisms, including infiltration of immunosuppressive cells, expression of immune checkpoint molecules, and enrichment of signal pathways related to cancer and immunosuppression. The nomogram basing on the hypoxia-related risk score model showed a good ability to predict prognosis and high clinical net benefits.ConclusionsThe hypoxia risk score model revealed a close relationship between hypoxia and tumor immune microenvironment. The current study potentially provides new insights of how hypoxia affects the prognosis, and may provide a new therapeutic target for patients with gastric cancer.

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Distinct Hypoxia-Related Gene Profiling Characterizes Clinicopathological Features and Immune Status of Mismatch Repair-Deficient Colon Cancer

“…Previous studies also identified that hypoxia could induce the high expression of immune checkpoint molecules, such as indoleamine 2,3-dioxygenase (IDO) and PD-L1 [ 50 , 51 ]. The expression of immune checkpoint molecules might be negatively associated with the infiltration of TILs and the prognosis in types of cancers [ 7 , 52 , 53 ].…”

“…However, approximately 60% of dMMR patients may still progress and experience resistance to the same regimens [ 4 ]. Thus, many studies have focused on conducting comprehensive genome-wide analysis to identify the underlying molecular mechanisms of poor response to ICIs and distinct outcomes in other types of human malignancy [ 5 – 7 ].…”

The Effect of Hypoxia and Hypoxia-Associated Pathways in the Regulation of Antitumor Response: Friends or Foes?

“…In the last decade, the application of hypoxia gene signatures to reflect the degree of tumor hypoxia has taken the literature by storm with published signatures covering almost every solid tumor type (9,106). In addition to that, there has been an escalating number of papers focused not only on designating the hypoxic state of a tumor, but also interrogating the immune populations and immune activation status of that tumor depending on its hypoxic phenotype (189)(190)(191)(192)(193)(194)(195)(196)(197). The process generally entails first deriving a hypoxia signature in the cancer type of interest, which often takes the route of narrowing down a list of hypoxia-related differentially expressed genes (DEGs) between normal and tumor tissue, then determining which genes are correlated with patient prognosis, be it overall survival or disease-free survival.…”