Department of General Practice, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China.
Department of Geriatrics, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China.
Front Immunol. 2023 Feb 3;14:1111494. doi: 10.3389/fimmu.2023.1111494. eCollection 2023.
Treatment of cancer with pyroptosis is an emerging strategy. Molecular subtypes based on pyroptosis-related genes(PRGs) seem to be considered more conducive to individualized therapy. It is meaningful to construct a pyroptosis molecular subtypes-related prognostic signature (PMSRPS) to predict the overall survival (OS) of patients with pancreatic adenocarcinoma(PAAD) and guide treatment.
Based on the transcriptome data of 23 PRGs, consensus clustering was applied to divide the TCGA and GSE102238 combined cohort into three PRGclusters. Prognosis-related differentially expressed genes(DEGs) among PRGclusters were subjected to LASSO Cox regression analysis to determine a PMSRPS. External cohort and experiments were conducted to verify this PMSRPS. The CIBERSORT algorithm, the ESTIMATE algorithm and the Immunophenoscore (IPS) were used to analyze the infiltrating abundance of immune cells, the tumor microenvironment (TME), and the response to immunotherapy, respectively. Wilcoxon analysis was used to compare tumor mutational burden (TMB) and RNA stemness scores (RNAss) between groups. RT-qPCR and functional experiments were used for evaluating the expression and function of SFTA2.
Based on three PRGclusters, 828 DEGs were obtained and a PMSRPS was subsequently constructed. In internal and external validation, patients in the high-risk group had significantly lower OS than those in the low-risk group and PMSRPS was confirmed to be an independent prognostic risk factor for patients with PAAD with good predictive performance. Immune cell infiltration abundance and TME scores indicate patients in the high-risk group have typical immunosuppressive microenvironment characteristics. Analysis of IPS suggests patients in the high-risk group responded better to novel immune checkpoint inhibitors (ICIs) than PD1/CTLA4. The high-risk group had higher TMB and RNAss. In addition, 10 potential small-molecule compounds were screened out. Finally, we found that the mRNA expression of SFTA2 gene with the highest risk coefficient in PMSRPS was significantly higher in PAAD than in paracancerous tissues, and knockdown of it significantly delayed the progression of PAAD.
PMSRPS can well predict the prognosis, TME and immunotherapy response of patients with PAAD, identify potential drugs, and provide treatment guidance based on individual needs.
利用细胞焦亡治疗癌症是一种新兴策略。基于与细胞焦亡相关基因（PRGs）的分子亚型似乎更有利于个体化治疗。构建细胞焦亡分子亚型相关预后签名（PMSRPS）来预测胰腺导管腺癌（PAAD）患者的总生存期（OS）并指导治疗具有重要意义。
基于 23 个 PRGs 的转录组数据，采用共识聚类将 TCGA 和 GSE102238 联合队列分为三个 PRGcluster。对 PRGcluster 之间的预后相关差异表达基因（DEGs）进行 LASSO Cox 回归分析，以确定 PMSRPS。外部队列和实验用于验证该 PMSRPS。使用 CIBERSORT 算法、ESTIMATE 算法和免疫评分（IPS）分别分析免疫细胞浸润丰度、肿瘤微环境（TME）和免疫治疗反应。Wilcoxon 分析用于比较组间肿瘤突变负担（TMB）和 RNA 干性评分（RNAss）。RT-qPCR 和功能实验用于评估 SFTA2 的表达和功能。
基于三个 PRGcluster，获得了 828 个 DEGs，随后构建了 PMSRPS。在内部和外部验证中，高危组患者的 OS 明显低于低危组，PMSRPS 被证实是 PAAD 患者的独立预后危险因素，具有良好的预测性能。免疫细胞浸润丰度和 TME 评分表明高危组患者具有典型的免疫抑制微环境特征。IPS 分析表明，高危组患者对新型免疫检查点抑制剂（ICIs）的反应优于 PD1/CTLA4。高危组的 TMB 和 RNAss 更高。此外，筛选出 10 种潜在的小分子化合物。最后，我们发现 PMSRPS 中风险系数最高的 SFTA2 基因的 mRNA 表达在 PAAD 中明显高于癌旁组织，并且敲低它可以显著延缓 PAAD 的进展。
PMSRPS 可以很好地预测 PAAD 患者的预后、TME 和免疫治疗反应，识别潜在药物，并根据个体需求提供治疗指导。
