Integrated Bioinformatical Analysis Identifies GIMAP4 as an Immune-Related Prognostic Biomarker Associated With Remodeling in Cervical Cancer Tumor Microenvironment.

Fangfang Xu,Shaohua Xu,Jiacheng Shen

doi:10.3389/fcell.2021.637400

Abstract

Tumor microenvironment (TME) is emerging as an essential part of cervical cancer (CC) tumorigenesis and development, becoming a hotspot of research these years. However, comprehending the specific composition of TME is still facing enormous challenges, especially the immune and stromal components. In this study, we downloaded the RNA-seq profiles and somatic mutation data of 309 CC cases from The Cancer Genome Atlas (TCGA) database, which were analyzed by integrative bioinformatical methods. Initially, ESTIMATE computational method was employed to calculate the amount of immune and stromal components. Then, based on the high- and low-immunity cohorts, we recognized the differentially expressed genes (DEGs) as well as the differentially mutated genes (DMGs). Additionally, we conducted an intersection analysis of DEGs and DMGs, ultimately determining an immune-related prognostic signature, GTPase, IMAP Family Member 4 (GIMAP4). Moreover, sequential analyses demonstrated that GIMAP4 was a protective factor in CC, positively correlated with the overall survival (OS) and negatively with distant metastasis. Besides, we utilized the Gene Set Enrichment Analysis (GSEA) to explore the enrichment-pathways in high and low-expression cohorts of GIMAP4. The results indicated that the genes of the high-expression cohort had a high enrichment in immune-related biological processes and metabolic activities in the low one. Furthermore, CIBERSORT analysis was applied to evaluate the proportion of tumor-infiltrating immune cells (TICs), illustrating that several activated TICs were strongly associated with GIMAP4 expression, which suggested that GIMAP4 had the potential to be an indicator for the immune state in TME of CC. Hence, GIMAP4 contributed to predicting the CC patients’ clinical outcomes, such as survival rate, distant metastasis and immunotherapy response. Moreover, GIMAP4 could serve as a promising biomarker for TME remodeling, suggesting the possible underlying mechanisms of tumorigenesis and CC progression, which may provide different therapeutic perceptions of CC, and therefore improve treatment.

Highlights

Cervical cancer (CC) is the fourth malignancy worldwide in the female reproductive system, representing a major global health challenge
We came to a conclusion that the immune component in Tumor microenvironment (TME) seemed to play a more critical part in the clinical outcomes of CC patients, including survival rate and M classification, illustrating that the immune component was closely related to the prognosis and the progression of CC, especially invasion and distant metastasis
Further CIBERSORT analysis for the ratio of tumor-infiltrating immune cells (TICs) confirmed the effect of GIMAP4 on TME, especially the immune component, and the results revealed that CD8 + T cells and CD4 + activated memory T cells were positively correlated with GIMAP4 expression in CC patients

Summary

Introduction

Cervical cancer (CC) is the fourth malignancy worldwide in the female reproductive system, representing a major global health challenge. The treatments for CC have remained unchanged for several decades, such as surgical treatment, cytotoxic chemotherapy, and radiotherapy, etc. These therapy approaches can hardly prevent the metastasis and recurrence in CC patients; new therapeutic strategies are urgently required to improve the poor prognosis. Despite checkpoint inhibitor-based immunotherapy is emerging as a novel therapeutic approach and has achieved enormous success in various kinds of cancer currently, the response of CC patients remains low, which restricts the development and application of immunotherapy in CC (Di et al, 2015; Herbst et al, 2016; Schachter et al, 2017).

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