Intratumoral IL-1R1 expression delineates a distinctive molecular subset with therapeutic resistance in patients with gastric cancer.
Intratumoral IL-1R1 expression delineates a distinctive molecular subset with therapeutic resistance in patients with gastric cancer.
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DOI：
10.1136/jitc-2021-004047
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发表时间：
2022-03
影响因子：
10.9
通讯作者：
Xu J
中科院分区：
文献类型：
--
作者：
Zhang P;Gu Y;Fang H;Cao Y;Wang J;Liu H;Zhang H;Li H;He H;Li R;Lin C;Xu J
IL-1R1作为IL-1α和IL-1β的主要受体，在肿瘤相关炎症中发挥重要作用，在多种癌症中显示出潜在的治疗潜力，目前已进入临床试验。然而，IL-1R1在胃癌(GC)中的表达谱和关键作用尚不清楚。本研究旨在探讨IL-1R1在GC中表达的预后意义及其对化疗和免疫治疗的预测价值。这项研究纳入了三个队列，包括来自中山医院的409个GC患者的肿瘤微阵列样本，来自癌症基因组图谱的341个转录数据，以及来自接受培溴利珠单抗治疗的45个患者的转录数据。直接从公共数据集中获取IL-1R1mRNA的表达，并用免疫组织化学方法检测肿瘤芯片上IL-1R1蛋白的表达。最后，我们分析了IL-1R1的表达与临床结果、免疫环境和基因组特征的关系。IL-1R1的高表达预示着预后不良，对5-氟尿嘧啶辅助化疗(ACT)和免疫检查点阻断(ICB)的反应均较差。IL-1R1促进了一种免疫抑制微环境，其特征是M2巨噬细胞上调和CD8+T细胞的耗尽。此外，IL-1R1的表达与GC靶向治疗相关的基因组改变有内在联系。IL-1R1可作为胃癌ACT和ICB的独立预测指标和预测生物标志物。此外，IL-1R1拮抗剂可能单独或与现有的治疗策略联合应用于GC。
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 The Cancer Genome Atlas, 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.
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影响因子：
4.6
作者：
Guo B;Fu S;Zhang J;Liu B;Li Z
通讯作者：
Li Z
Interleukin-1家族：回到未来。
影响因子：
32.4
作者：
Garlanda C;Dinarello CA;Mantovani A
通讯作者：
Mantovani A
影响因子：
11.5
作者：
Kubota, Yohei;Kawazoe, Akihito;Shitara, Kohei
通讯作者：
Shitara, Kohei
影响因子：
8.8
作者：
De Vita, F;Orditura, M;Bianco, AR
通讯作者：
Bianco, AR
影响因子：
7.2
作者：
Isambert N;Hervieu A;Rébé C;Hennequin A;Borg C;Zanetta S;Chevriaux A;Richard C;Derangère V;Limagne E;Blanc J;Bertaut A;Ghiringhelli F
通讯作者：
Ghiringhelli F