目的:在胃癌(GC)患者中观察到的对免疫治疗的可变反应可归因于肿瘤微环境的复杂性。谷胱甘肽(GSH)代谢显着影响胃癌的发生和进展。因此,靶向GSH代谢有望提高免疫检查点抑制剂(ICIs)的有效性.
方法:我们研究了16个与GSH代谢相关的基因,来自MSigDB数据库,使用来自TCGA的泛癌症数据集。鉴定最具代表性的预后相关基因用于进一步分析。ScRNA测序分析用于探索GC的肿瘤异质性,结果通过多重免疫组织化学(mIHC)证实。
结果:通过DEG,拉索,单变量和多变量Cox回归分析,和生存分析,我们鉴定了GGT5为GSH代谢中的hub基因,具有促进GC的潜力。CombiningCIBERSORT,ssGSEA,和scRNA分析,我们构建了GC的免疫结构。分离T细胞亚群,揭示了GGT5和记忆CD8+T细胞之间的强关联。此外,收集10例接受免疫治疗的GC患者的标本.mIHC用于评估GGT5和记忆CD8+T细胞标志物的表达水平。我们的结果建立了之间的ggt5表达的正相关,记忆CD8+T细胞的富集,和免疫疗法的次优反应。
结论:我们的研究确定了GGT5,GSH代谢的中心基因,作为抑制GC患者免疫疗法反应的潜在治疗靶点。这些发现为优化GC的免疫治疗策略提供了新的见解。
OBJECTIVE: The variable responses to immunotherapy observed in gastric cancer (GC) patients can be attributed to the intricate nature of the tumor microenvironment. Glutathione (GSH) metabolism significantly influences the initiation and progression of gastric cancer. Consequently, targeting GSH metabolism holds promise for improving the effectiveness of Immune checkpoints inhibitors (ICIs).
METHODS: We investigated 16 genes related to GSH metabolism, sourced from the MSigDB database, using pan-cancer datasets from TCGA. The most representative prognosis-related gene was identified for further analysis. ScRNA-sequencing analysis was used to explore the tumor heterogeneity of GC, and the results were confirmed by Multiplex immunohistochemistry (mIHC).
RESULTS: Through DEGs, LASSO, univariate and multivariate Cox regression analyses, and survival analysis, we identified GGT5 as the hub gene in GSH metabolism with the potential to promote GC. Combining CIBERSORT, ssGSEA, and scRNA analysis, we constructed the immune architecture of GC. The subpopulations of T cells were isolated, revealing a strong association between GGT5 and memory CD8+ T cells. Furthermore, specimens from 10 GC patients receiving immunotherapy were collected. mIHC was used to assess the expression levels of GGT5 and memory CD8+ T cell markers. Our results established a positive correlation between GGT5 expression, the enrichment of memory CD8+ T cells, and a suboptimal response to immunotherapy.
CONCLUSIONS: Our study identifies GGT5, a hub gene in GSH metabolism, as a potential therapeutic target for inhibiting the response to immunotherapy in GC patients. These findings offer new insights into strategies for optimizing immunotherapy of GC.