Department of Biochemistry and Molecular Biology, Fudan University School of Basic Medical Sciences, Shanghai, China.
Department of General Surgery, Zhongshan Hospital Fudan University, Shanghai, China.
J Immunother Cancer. 2022 Feb;10(2). doi: 10.1136/jitc-2021-004047.
With the essential role of interleukin-1 signaling in cancer-related inflammation, IL-1R1, the main receptor for both IL-1α and IL-1β, demonstrated therapeutic potential in several types of cancer, which has been put into clinical trials. However, the expression profile and critical role of IL-1R1 in gastric cancer (GC) remain obscure. This study aimed to investigate the prognostic significance of IL-1R1 expression and its predictive value for chemotherapy and immunotherapy in GC.
The study enrolled three cohorts, consisting of 409 tumor microarray specimens of GC patients from Zhongshan Hospital, 341 transcriptional data from , and 45 transcriptional data from patients treated with pembrolizumab. IL-1R1 mRNA expression was directly acquired from public datasets, and we also detected IL-1R1 protein expression on tumor microarray by immunohistochemistry. Finally, the associations of IL-1R1 expression with clinical outcomes, immune contexture, and genomic features were analyzed.
High IL-1R1 expression predicted poor prognosis and inferior responsiveness to both 5-fluorouracil-based adjuvant chemotherapy (ACT) and immune checkpoint blockade (ICB). IL-1R1 fostered an immunosuppressive microenvironment characterized by upregulated M2 macrophages and exhausted CD8 T cells infiltration. Moreover, the expression of IL-1R1 was intrinsically linked to genomic alterations associated with targeted therapies in GC.
IL-1R1 served as an independent prognosticator and predictive biomarker for ACT and ICB in GC. Furthermore, IL-1R1 antagonists could be a novel agent alone or combined with current therapeutic strategies in GC.
白细胞介素-1 信号在癌症相关炎症中起着重要作用，IL-1R1 是 IL-1α 和 IL-1β 的主要受体，在几种类型的癌症中显示出治疗潜力，这些潜力已被纳入临床试验。然而，IL-1R1 在胃癌（GC）中的表达谱和关键作用仍不清楚。本研究旨在探讨 IL-1R1 表达的预后意义及其对 GC 化疗和免疫治疗的预测价值。
该研究纳入了三个队列，包括来自中山医院的 409 例 GC 患者肿瘤微阵列标本、341 例转录数据和 45 例接受 pembrolizumab 治疗的患者转录数据。IL-1R1 mRNA 表达直接从公共数据集获取，我们还通过免疫组织化学检测肿瘤微阵列上的 IL-1R1 蛋白表达。最后，分析了 IL-1R1 表达与临床结局、免疫结构和基因组特征的关系。
高 IL-1R1 表达预示着预后不良，对 5-氟尿嘧啶为基础的辅助化疗（ACT）和免疫检查点阻断（ICB）均反应不佳。IL-1R1 促进了以 M2 巨噬细胞上调和耗竭的 CD8 T 细胞浸润为特征的免疫抑制微环境。此外，IL-1R1 的表达与 GC 中与靶向治疗相关的基因组改变内在相关。
IL-1R1 是 GC 中 ACT 和 ICB 的独立预后标志物和预测生物标志物。此外，IL-1R1 拮抗剂可作为一种单独或与现有治疗策略联合应用于 GC 的新型药物。
