Department of Gastric Surgery, Fujian Medical University Union Hospital, Fuzhou, China.
Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou, China.
Theranostics. 2024 May 5;14(7):2915-2933. doi: 10.7150/thno.93124. eCollection 2024.
Pyroptosis plays a crucial role in immune responses. However, the effects of pyroptosis on tumor microenvironment remodeling and immunotherapy in gastric cancer (GC) remain unclear. Large-sample GEO data (GSE15459, GSE54129, and GSE62254) were used to explore the immunoregulatory roles of pyroptosis. TCGA cohort was used to elucidate multiple molecular events associated with pyroptosis, and a pyroptosis risk score (PRS) was constructed. The prognostic performance of the PRS was validated using postoperative GC samples from three public databases (n=925) and four independent Chinese medical cohorts (n=978). Single-cell sequencing and multiplex immunofluorescence were used to elucidate the immune cell infiltration landscape associated with PRS. Patients with GC who received neoadjuvant immunotherapy (n=48) and those with GC who received neoadjuvant chemotherapy (n=49) were enrolled to explore the value of PRS in neoadjuvant immunotherapy. GC pyroptosis participates in immune activation in the tumor microenvironment and plays a powerful role in immune regulation. PRS, composed of four pyroptosis-related differentially expressed genes (, , , and ), is a reliable and independent biomarker for GC. PRS is associated with an activated pyroptosis pathway and greater infiltration of anti-tumor immune cells, including more effector and CD4+ T cells, and with the polarization of tumor-associated macrophages in the tumor center. Importantly, PRS marks the effectiveness of neoadjuvant immunotherapy and enables screening of GC patients with combined positive score ≥1 who benefit from neoadjuvant immunotherapy. Our study demonstrated that pyroptosis activates immune processes in the tumor microenvironment. A low PRS correlates with enhanced infiltration of anti-tumor immune cells at the tumor site, increased pyroptotic activity, and improved patient outcomes. The constructed PRS can be used as an effective quantitative tool for pyroptosis analysis to guide more effective immunotherapeutic strategies for patients with GC.
细胞焦亡在免疫反应中起着至关重要的作用。然而，细胞焦亡对胃癌（GC）肿瘤微环境重塑和免疫治疗的影响尚不清楚。本研究使用了大量的 GEO 数据（GSE15459、GSE54129 和 GSE62254）来探索细胞焦亡的免疫调节作用。TCGA 队列用于阐明与细胞焦亡相关的多种分子事件，并构建了细胞焦亡风险评分（PRS）。使用来自三个公共数据库（n=925）和四个独立的中国医疗队列（n=978）的术后 GC 样本验证了 PRS 的预后性能。单细胞测序和多重免疫荧光用于阐明与 PRS 相关的免疫细胞浸润景观。纳入了 48 名接受新辅助免疫治疗的 GC 患者和 49 名接受新辅助化疗的 GC 患者，以探索 PRS 在新辅助免疫治疗中的价值。GC 细胞焦亡参与肿瘤微环境中的免疫激活，并在免疫调节中发挥强大作用。PRS 由四个与细胞焦亡相关的差异表达基因（、、、和）组成，是 GC 的一种可靠且独立的生物标志物。PRS 与激活的细胞焦亡途径和更多抗肿瘤免疫细胞的浸润相关，包括更多的效应 T 细胞和 CD4+T 细胞，以及肿瘤中心肿瘤相关巨噬细胞的极化。重要的是，PRS 标志着新辅助免疫治疗的有效性，并能够筛选出联合阳性评分≥1 的 GC 患者，这些患者从新辅助免疫治疗中受益。本研究表明，细胞焦亡激活了肿瘤微环境中的免疫过程。低 PRS 与肿瘤部位抗肿瘤免疫细胞浸润增加、细胞焦亡活性增强和患者预后改善相关。构建的 PRS 可作为细胞焦亡分析的有效定量工具，以指导 GC 患者更有效的免疫治疗策略。
