ERO1L shapes the immune-suppressive tumor microenvironment and is a potential biomarker for immunotherapy response in lung adenocarcinoma.

e21006 Background: Recently, immune checkpoint inhibitors have led to a paradigm shift in treatment for patients with lung adenocarcinoma (LUAD), however, the identification of biomarkers to enable patient selection is urgently required. The endoplasmic reticulum oxidoreductin-1-like ( ERO1L) gene encodes an endoplasmic reticulum luminal localized glycoprotein known to associated with hypoxia. The role of ERO1L in the crafting of the tumor immune microenvironment (TIME) is yet to be elucidated. Methods: 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 ERO1L 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. Results: We identified ERO1L to be an oncogene, the mRNA expression of which is significantly higher in LUAD compared with normal tissues. High expression levels of ERO1L were associated with poor prognoses in terms of overall survival (HR: 1.52, 95% CI: 1.27-1.82) and progression-free survival (HR: 1.93, 95% CI: 1.47-2.53). This overexpression was found to be a result of hypomethylation of the ERO1L promoter. Overexpression of ERO1L resulted in an immune-suppressive TIME via the recruitment of immune-suppressive cells including regulatory T cells (Spearman’s ρ = 0.199, p < 0.001) cancer associated fibroblasts (ρ = 0.286, p < 0.001), and myeloid-derived suppressor cells (ρ = 0.423, p < 0.001), and also indicated the polarization of M1-type to M2-type macrophage. On the contrary, overexpression of ERO1L was closely associated with deficiency of immune-active cells including B cells (ρ = -0.250, p < 0.001), CD8+ T cells (ρ = -0.299, p < 0.001), and NK cells (ρ = -0.258, p < 0.001). Using the Tumor Immune Dysfunction and Exclusion (TIDE) framework, it was identified that patients in the ERO1Lhigh group possessed a significantly lower response rate (31.0%) to immunotherapy compared with the ERO1Llow group (86.0%). Mechanistic analysis revealed that overexpression of ERO1L was associated with the upregulation of JAK-STAT (NES = 1.65, FDR q-value = 0.0) and NF-κB (NES = 2.03, FDR q-value = 0.0) signaling pathways, thus affecting chemokine and cytokine patterns in the TIME. Conclusions: Our study provides clear insight into the potential role of ERO1L in tumor immunology. Overexpression of ERO1L was indicative of a hypoxia-induced immune-suppressive TIME, which was shown to confer resistance to immunotherapy in patients with LUAD. ERO1L was shown to mediate cytokine and chemokine patterns in the TIME, which were resulted from activations of JAK-STAT and NF-κB signaling pathways.