AUTHOR=Liu Lihui , Wang Chao , Li Sini , Qu Yan , Xue Pei , Ma Zixiao , Zhang Xue , Bai Hua , Wang Jie 

TITLE=ERO1L Is a Novel and Potential Biomarker in Lung Adenocarcinoma and Shapes the Immune-Suppressive Tumor Microenvironment

JOURNAL=Frontiers in Immunology

VOLUME=12

YEAR=2021

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2021.677169

DOI=10.3389/fimmu.2021.677169

ISSN=1664-3224

ABSTRACT=<sec><title>Background</title><p>The endoplasmic reticulum oxidoreductin-1-like (<italic>ERO1L</italic>) gene encodes an endoplasmic reticulum luminal localized glycoprotein known to associated with hypoxia, however, the role of <italic>ERO1L</italic> in shaping the tumor immune microenvironment (TIME) is yet to be elucidated in lung adenocarcinoma (LUAD).</p></sec><sec><title>Methods</title><p>In this study, raw datasets (including RNA-seq, methylation, sgRNA-seq, phenotype, and survival data) were obtained from public databases. This data was analyzed and used to explore the biological landscape of <italic>ERO1L</italic> in immune infiltration. Expression data was used to characterize samples. Using gene signatures and cell quantification, stromal and immune infiltration was determined. These findings were used to predict sensitivity to immunotherapy.</p></sec><sec><title>Results</title><p>This study found that <italic>ERO1L</italic> was significantly overexpressed in LUAD in comparison to normal tissue. This overexpression was found to be a result of hypomethylation of the <italic>ERO1L</italic> promoter. Overexpression of <italic>ERO1L</italic> resulted in an immune-suppressive TIME <italic>via</italic> the recruitment of immune-suppressive cells including regulatory T cells (T<sub>regs</sub>), cancer associated fibroblasts, M2-type macrophages, and myeloid-derived suppressor cells. Using the Tumor Immune Dysfunction and Exclusion (TIDE) framework, it was identified that patients in the <italic>ERO1L</italic><sup>high</sup> group possessed a significantly lower response rate to immunotherapy in comparison to the <italic>ERO1L</italic><sup>low</sup> group. Mechanistic analysis revealed that overexpression of <italic>ERO1L</italic> was associated with the upregulation of JAK-STAT and NF-κB signaling pathways, thus affecting chemokine and cytokine patterns in the TIME.</p></sec><sec><title>Conclusions</title><p>This study found that overexpression of <italic>ERO1L</italic> was associated with poor prognoses in patients with LUAD. Overexpression of <italic>ERO1L</italic> was indicative of a hypoxia-induced immune-suppressive TIME, which was shown to confer resistance to immunotherapy in patients with LUAD. Further studies are required to assess the potential role of <italic>ERO1L</italic> as a biomarker for immunotherapy efficacy in LUAD.</p></sec>