Department of Gastric Surgery, Fudan University Shanghai Cancer Center, 200030, Shanghai, China.
Department of Oncology, Shanghai Medical College of Fudan University, 200030, Shanghai, China.
Mol Med. 2022 May 4;28(1):47. doi: 10.1186/s10020-022-00475-8.
Receptor-interacting protein kinase 2 (RIPK2, also known as RIP2) was reported to be associated with bacterial infections as well as inflammatory responses. However, the role of RIPK2 in prognosis and immunotherapy response is yet to be elucidated in human pan-cancer.
In this study, we investigated the expression, gene alteration landscape and prognostic value of RIPK2 in 33 cancers through various databases including Ualcan, cBioportal and Gene Expression Profiling Interactive Analysis 2 (GEPIA2). Then, the correlation between RIPK2 and immune infiltration, immune score, stromal score, and ESTIMATE score was investigated in the Cancer Genome Atlas (TCGA) and tumor immune estimation resource (TIMER) databases. Independent cohorts were utilized to explore the role of RIPK2 in tumor immunotherapy response. Furthermore, Gene set enrichment analysis (GSEA) was conducted to explore the mechanisms by which RIPK2 regulates immune therapy resistance. Single-cell RNA-seq datasets were used to analyze the expression level of RIPK2 on different immune cells. Moreover, CellMiner database was used to explore the relationship between RIPK2 expression with drug response.
Compared with normal tissue, tumor tissue had a higher expression level of RIPK2 in various cancers. Survival analysis showed that high expression of RIPK2 associated with poor prognosis in numerous cancers. RIPK2 was found to promote a series of immune cell infiltration and B cells, macrophages, and neutrophils were significantly positively correlated with the expression of RIPK2. Moreover, RIPK2 affected immune score, stromal score and ESTIMATE score for a wide range of cancers. In the vast majority of 33 cancers, gene co-expression analysis showed that RIPK2 was positively correlated with the expression of immune checkpoint markers, such as PDCD1 (PD-1), CD274 (PD-L1), CTLA4 and TIGIT. RIPK2 aggravated cytotoxic T lymphocyte (CTL) dysfunction and related to the poor efficacy of immune checkpoint blockade in skin cutaneous melanoma (SKCM) and kidney renal clear cell carcinoma (KIRC). High expression of RIPK2 promoted innate immunotherapy resistance and adaptive immunotherapy resistance through IL-6/JAK/STAT3 signaling, interferon-gamma response, and interferon-alpha response pathway.
These results confirmed that RIPK2 could serve as a prognostic biomarker and promoted immune therapy resistance via triggering cytotoxic T lymphocytes dysfunction.
受体相互作用蛋白激酶 2（RIPK2，也称为 RIP2）已被报道与细菌感染以及炎症反应有关。然而，RIPK2 在人类泛癌中的预后和免疫治疗反应中的作用尚不清楚。
在这项研究中，我们通过 Ualcan、cBioportal 和基因表达谱交互分析 2（GEPIA2）等各种数据库，研究了 RIPK2 在 33 种癌症中的表达、基因改变景观和预后价值。然后，我们在癌症基因组图谱（TCGA）和肿瘤免疫估计资源（TIMER）数据库中研究了 RIPK2 与免疫浸润、免疫评分、基质评分和 ESTIMATE 评分的相关性。利用独立队列探索 RIPK2 在肿瘤免疫治疗反应中的作用。此外，进行基因集富集分析（GSEA）以探讨 RIPK2 调节免疫治疗耐药的机制。单细胞 RNA-seq 数据集用于分析不同免疫细胞中 RIPK2 的表达水平。此外，CellMiner 数据库用于探讨 RIPK2 表达与药物反应的关系。
与正常组织相比，各种癌症中的肿瘤组织 RIPK2 的表达水平更高。生存分析表明，RIPK2 高表达与许多癌症的不良预后相关。研究发现，RIPK2 促进了一系列免疫细胞浸润，B 细胞、巨噬细胞和中性粒细胞与 RIPK2 的表达呈显著正相关。此外，RIPK2 广泛影响了 33 种癌症的免疫评分、基质评分和 ESTIMATE 评分。在 33 种癌症中的绝大多数中，基因共表达分析表明，RIPK2 与免疫检查点标志物（如 PDCD1（PD-1）、CD274（PD-L1）、CTLA4 和 TIGIT）的表达呈正相关。RIPK2 加重了细胞毒性 T 淋巴细胞（CTL）功能障碍，与皮肤黑色素瘤（SKCM）和肾透明细胞癌（KIRC）中免疫检查点阻断的疗效不佳有关。RIPK2 通过 IL-6/JAK/STAT3 信号、干扰素-γ反应和干扰素-α反应途径促进先天免疫治疗耐药和适应性免疫治疗耐药。
这些结果证实，RIPK2 可作为预后生物标志物，并通过触发细胞毒性 T 淋巴细胞功能障碍来促进免疫治疗耐药。
