Ferroptosis Driver SOCS1 and Suppressor FTH1 Independently Correlate With M1 and M2 Macrophage Infiltration in Head and Neck Squamous Cell Carcinoma.

Xue-Lan Zeng,Wei Sun,Lin Chen,Zhang-Wei Hu,Wei-Ping Wen,Yi-Hui Wen,Ren-Qiang Ma

doi:10.3389/fcell.2021.727762

Abstract

ObjectiveTo investigate the role of ferroptosis, an iron-dependent form of non-apoptotic cell death, in the head and neck squamous cell carcinoma (HNSCC) immune microenvironment.Materials and MethodsA list of ferroptosis-related genes was obtained from the FerrDb database. Gene expression data were acquired from the cancer genome atlas (TCGA) and analyzed using the R language. Protein–protein interaction analysis was conducted using STRING and GeneMANIA. The correlations between gene expression levels and a patient’s survival were analyzed using GEPIA, the Kaplan–Meier estimate, and a multivariate Cox proportional hazards model. The expression results were verified using Oncomine and Human Protein Atlas data. We used the TIMER, GEPIA2, GEPIA2021, and TIMER2 databases to investigate the relationships between gene expression and infiltrating immune cells.ResultsAnalysis of differentially expressed genes (DEGs) identified nine each ferroptosis drivers and ferroptosis suppressors, among which four genes correlated with survival as follows: two drivers (SOCS1, CDKN2A) associated with better survival and two suppressors (FTH1, CAV1) associated with poorer survival. Multivariate Cox survival analysis identified SOCS1 and FTH1 as independent prognostic factors for HNSCC, and their higher expression levels were verified using Oncomine and HPA data. The results acquired using TIMER, GEPIA2, GEPIA2021, and TIMER2 data revealed that the driver SOCS1 and the suppressor FTH1 independently correlated with M1 and M2 macrophage infiltration.ConclusionsThe ferroptosis driver SOCS1 and suppressor FTH1 are independent prognostic factors and that correlate with M1 and M2 macrophage infiltration in HNSCC. Targeting ferroptosis-immunomodulation may serve as a strategy to enhance the activity of immunotherapy.

Highlights

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide (Siegel et al, 2020)
The gene expression data and clinical characteristics of 528 HNSCC, 2 metastatic and 82 normal tissue samples from the the cancer genome atlas (TCGA) database were included in the study
To explore the differentially expressed ferroptosis-related genes in HNSCC, mRNA expression was analyzed with the TCGA database

Summary

Introduction

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide (Siegel et al, 2020). Despite great progress in immunotherapy, only a small subset of patients with HNSCC respond to immune checkpoint inhibitors (Johnson et al, 2020), mainly because of the immunosuppressive microenvironment associated with tumor immunosuppressive cells, including tumor-associated macrophages (TAMs, called M2d), regulatory T cells (Tregs), and other immunomodulatory cells (Watermann et al, 2021). In tumor microenvironment ferroptosis seems to have a dual role in tumor promotion and suppression, depending on releasing damage-associated molecular patterns and activating immune response (Chen et al, 2021). Ferroptosis is thought to have synergistic effects to suppress tumor growth in combination with other antitumor drugs, including immune checkpoint inhibitors (Roh et al, 2016; Wang et al, 2019). We previously found that the expression of the ferroptosis suppressor gene FTH1 positively correlated with macrophages in most solid tumors (Hu et al, 2021), indicating an important role for ferroptosis in regulating tumor immunity

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