胃癌免疫原性细胞死亡相关亚型的鉴定及预后标志物的建立。

Identification of Immunogenic Cell-Death-Related Subtypes and Development of a Prognostic Signature in Gastric Cancer.

机构信息

Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gastrointestinal Cancer Center, Ward I, Peking University Cancer Hospital & Institute, Beijing 100142, China.

出版信息

Biomolecules. 2023 Mar 14;13(3):528. doi: 10.3390/biom13030528.

BACKGROUND

Immunogenic cell death (ICD) is considered a promising type of regulated cell death and exerts effects by activating the adaptive immune response, reshaping the tumor environment (TME) and improving therapeutic efficacy. However, the potential roles and prognostic value of ICD-associated genes in gastric cancer (GC) remain unclear.

METHODS

The RNA expression data and clinical information of 1090 GC patients from six cohorts were collected. Consensus clustering was used to identify three distinct molecular subtypes. Then, a robust prognostic ICD_score for predicting prognosis was built via WGCNA and LASSO Cox regression according to the TCGA cohort, and the predictive capability of the ICD_score in GC patients was validated in the other cohorts. ICD-related immune features were analyzed using a CIBERSORT method and verified by immunofluorescence.

RESULTS

We found that ICD-related gene variations were correlated with clinical outcomes, tumor immune microenvironment (TIME) characteristics and treatment response. We then constructed an ICD signature that classifies cases as low- and high-ICD_score groups. The high-ICD_score group indicates unfavorable OS, a more advanced TNM stage, and presents an immune-suppressed phenotype, which has more infiltrations of pro-tumor immune cells, such as macrophages, which was verified by immunofluorescence. In addition, a nomogram containing the ICD_score showed a high predictive accuracy with AUCs of 0.715, 0.731 and 0.8 on Years 1, 3, and 5.

CONCLUSION

We performed the first and synthesis ICD analysis in GC and built a clinical application tool based on the ICD signature, which paved a new path for assessing prognosis and guiding individual treatment.

背景

免疫原性细胞死亡（ICD）被认为是一种有前途的调控细胞死亡方式，通过激活适应性免疫反应、重塑肿瘤微环境（TME）和提高治疗效果来发挥作用。然而，ICD 相关基因在胃癌（GC）中的潜在作用和预后价值仍不清楚。

方法

收集了来自六个队列的 1090 名 GC 患者的 RNA 表达数据和临床信息。采用共识聚类法识别出三个不同的分子亚型。然后，根据 TCGA 队列，通过 WGCNA 和 LASSO Cox 回归构建了一个稳健的预后 ICD_score，用于预测预后，并在其他队列中验证了 ICD_score 在 GC 患者中的预测能力。使用 CIBERSORT 方法分析了与 ICD 相关的免疫特征，并通过免疫荧光进行了验证。

结果

我们发现 ICD 相关基因的变化与临床结局、肿瘤免疫微环境（TIME）特征和治疗反应相关。我们构建了一个 ICD 特征，将病例分为低和高 ICD_score 组。高 ICD_score 组表示 OS 不良、更晚期的 TNM 分期和免疫抑制表型，其具有更多的促肿瘤免疫细胞浸润，如巨噬细胞，这通过免疫荧光得到了验证。此外，包含 ICD_score 的列线图在第 1、3 和 5 年的 AUC 分别为 0.715、0.731 和 0.8，具有较高的预测准确性。