Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Rui Jin Hospital, School of Medicine and School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China.
Front Immunol. 2024 Nov 1;15:1451796. doi: 10.3389/fimmu.2024.1451796. eCollection 2024.
Immunogenic cell death (ICD) is capable of activating the anti-tumor immune response of the organism; however, it is concurrently a complex process involving multiple factors. The specific factors that impact the occurrence of ICD remain undefined.
Through cluster analysis, patient specimens retrieved from the TARGET, TCGA, and GEO AML databases were categorized into two subtypes based on the expression levels of ICD-related genes: ICD-high and ICD-low. We compared the prognostic survival outcomes, pathway enrichment analysis, and immune cell infiltration between these two subtypes. Additionally, we identified factors related to AML development from multiple databases and verified the role of these factors both in vivo and in vitro in activating the immune response during the occurrence of ICD.
In the ICD-high subtype, there was a notable increase in the abundance of immune cell populations, along with the enrichment of pathways pertinent to the activation of various immune cells. Despite these immunological enhancements, this subgroup demonstrated a poorer prognosis. This phenomenon was consistently observed across various additional AML datasets, leading us to hypothesize that elevated expression of ICD genes does not invariably correlate with a favorable prognosis. Notably, STK10 exhibited elevated expression in AML, was associated with a poor prognosis, and showed synchronous expression patterns with ICD genes. Inhibition of STK10 led to the activation of ICD and the induction of an antitumor response. Moreover, when combined with other ICD inducers, it produced a synergistic anti-tumor effect. Our results reveal the impact of STK10 on ICD and underscore its key role in initiating ICD.
免疫原性细胞死亡（ICD）能够激活机体的抗肿瘤免疫反应；然而，这是一个涉及多种因素的复杂过程。影响 ICD 发生的具体因素尚不清楚。
通过聚类分析，根据 ICD 相关基因的表达水平，将 TARGET、TCGA 和 GEO AML 数据库中患者标本分为两个亚型：ICD-高和 ICD-低。我们比较了这两种亚型的预后生存结局、通路富集分析和免疫细胞浸润。此外，我们从多个数据库中确定了与 AML 发展相关的因素，并在体内和体外验证了这些因素在 ICD 发生过程中激活免疫反应的作用。
在 ICD-高亚型中，免疫细胞群体的丰度显著增加，同时与激活各种免疫细胞的途径富集。尽管存在这些免疫学增强，但该亚组的预后较差。这种现象在多个额外的 AML 数据集上都得到了观察，使我们假设 ICD 基因的高表达并不一定与良好的预后相关。值得注意的是，STK10 在 AML 中表达上调，与预后不良相关，并且与 ICD 基因具有同步表达模式。抑制 STK10 导致 ICD 激活并诱导抗肿瘤反应。此外，当与其他 ICD 诱导剂联合使用时，它会产生协同的抗肿瘤作用。我们的研究结果揭示了 STK10 对 ICD 的影响，并强调了它在启动 ICD 中的关键作用。
