Metabolic Molecule PLA2G2D Is a Potential Prognostic Biomarker Correlating With Immune Cell Infiltration and the Expression of Immune Checkpoint Genes in Cervical Squamous Cell Carcinoma.

Hong Liu,Haihong Zeng,Chun Gao,Yifan Yang,Tong Zhu,Hui Wang,Liting Liu,Ruiyi Xu,Yafei Huang

doi:10.3389/fonc.2021.755668

Abstract

Cervical squamous cell carcinoma (CSCC) is the major pathological type of cervical cancer (CC), the second most prevalent reproductive system malignant tumor threatening the health of women worldwide. The prognosis of CSCC patients is largely affected by the tumor immune microenvironment (TIME); however, the biomarker landscape related to the immune microenvironment of CSCC and patient prognosis is less characterized. Here, we analyzed RNA-seq data of CSCC patients from The Cancer Genome Atlas (TCGA) database by dividing it into high- and low-immune infiltration groups with the MCP-counter and ESTIMATE R packages. After combining weighted gene co-expression network analysis (WGCNA) and differentially expressed gene (DEG) analysis, we found that PLA2G2D, a metabolism-associated gene, is the top gene positively associated with immune infiltration and patient survival. This finding was validated using data from The Cancer Genome Characterization Initiative (CGCI) database and further confirmed by quantitative reverse transcription-polymerase chain reaction (qRT-PCR). Finally, multiplex immunohistochemistry (mIHC) was performed to confirm the differential infiltration of immune cells between PLA2G2D-high and PLA2G2D-low tumors at the protein level. Our results demonstrated that PLA2G2D expression was significantly correlated with the infiltration of immune cells, especially T cells and macrophages. More importantly, PLA2G2D-high tumors also exhibited higher infiltration of CD8+ T cells inside the tumor region than PLA2G2D-low tumors. In addition, PLA2G2D expression was found to be positively correlated with the expression of multiple immune checkpoint genes (ICPs). Moreover, based on other immunotherapy cohort data, PLA2G2D high expression is correlated with increased cytotoxicity and favorable response to immune checkpoint blockade (ICB) therapy. Hence, PLA2G2D could be a novel potential biomarker for immune cell infiltration, patient survival, and the response to ICB therapy in CSCC and may represent a promising target for the treatment of CSCC patients.

Highlights

Cervical cancer (CC) is the fourth common malignant disease for female with an estimated 604,000 new cases and 342,000 deaths worldwide in 2020 [1]
The MCP-counter, a widely used algorithm, was used to evaluate the level of immune infiltration for each sample, according to which Cervical squamous cell carcinoma (CSCC) patients were divided into high- and low-immune infiltration clusters based on the unsupervised stratification method (Figure 1A)
The results demonstrated that the high-immune infiltration cluster determined by the MCP-counter had significantly higher survival than the low-immune infiltration cluster in CSCC (Figure 1B)

Summary

Introduction

Cervical cancer (CC) is the fourth common malignant disease for female with an estimated 604,000 new cases and 342,000 deaths worldwide in 2020 [1]. Cervical squamous cell carcinoma (CSCC) and adenocarcinoma are the most common pathological types accounting for approximately 70% and 25% of all CC, respectively [2]. Despite the substantial efforts being made in promoting HPV vaccination and early screening, the incidence of CC remains alarming in developing countries [2]. Current therapies for CC including surgical treatment, chemotherapy, and radiotherapy have greatly improved the clinical outcome of CC; the therapeutic efficacy remains limited for patients with advanced and distant conditions, which estimated a median overall survival of 17 months and 5-year survival of 17% [4, 5]. There is an urgent need for developing novel therapeutic strategies that can effectively treat these patients [6, 7]

Methods

Results

Conclusion