ERO1A drives immunosuppression and attenuates response to immune checkpoint blockade

Immunophenotyping of tumor microenvironment (TME) is crucial for immunotherapy efficacy in patients with solid tumours. However, strategies to characterize TME are largely limited with huge heterogeneity. We show that endoplasmic reticular oxidoreductase-1a (ERO1A) induces an immune-suppressive TME and resistance to PD-1 blockade by promoting endoplasmic reticulum (ER) stress response. Single-cell RNA sequencing analyses confirm that ERO1A is correlated with immunosuppression and dysfunction of CD8+ T cell along anti-PD-1 treatment. Ablation of Ero1a in tumours promotes the infiltration of lymphocytes as well as cytotoxicity of CD8+ T cells and enhances response to anti-PD-1 treatment in mouse models. Overall design: To dissect the cellular and molecular changes of the TME during immunotherapy, we performed scRNA-seq analyses of tumours from wild type mice (n=5) and Ero1a KO mice (n=5).

肿瘤微环境（Tumor Microenvironment, TME）的免疫表型分析对于实体瘤患者的免疫治疗疗效至关重要。然而，当前用于表征TME的策略受其高度异质性的显著限制。本研究发现，内质网氧化还原酶-1a（ERO1A）可通过激活内质网（ER）应激反应，诱导形成免疫抑制性肿瘤微环境并引发PD-1阻断治疗耐药。单细胞RNA测序分析证实，在抗PD-1治疗过程中，ERO1A表达与免疫抑制及CD8+T细胞功能失调呈显著相关。在小鼠模型中，肿瘤组织内Ero1a的敲除可促进淋巴细胞浸润，增强CD8+T细胞的细胞毒性，并提升对抗PD-1治疗的响应效果。
实验整体设计：为解析免疫治疗过程中TME的细胞与分子变化，我们对野生型小鼠（n=5）及Ero1a基因敲除小鼠（n=5）的肿瘤组织开展了单细胞RNA测序（scRNA-seq）分析。