Li Chenlu, Pan Jingjing, Jiang Yinyan, Wu Yanzhi, Jin Zhenlin, Chen Xupeng
Department of Gastroenterology, Affiliated Yueqing Hospital, Wenzhou Medical University, Wenzhou, China.
Department of Laboratory Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
Front Genet. 2022 Mar 21;13:788670. doi: 10.3389/fgene.2022.788670. eCollection 2022.
Triple-negative breast cancer (TNBC) is associated with poor prognosis and invalid therapeutical response to immunotherapy due to biological heterogeneity. There is an urgent need to screen for reliable indices, especially immunotherapy-associated biomarkers that can predict patient outcomes. Pyroptosis, as an inflammation-induced type of programmed cell death, is shown to create a tumor-suppressive environment and improve the chemotherapeutic response in multiple tumors. However, the specific therapeutic effect of pyroptosis in TNBC remains unclear. In this study, we present a consensus clustering by pyroptosis-related signatures of 119 patients with TNBC into two subtypes (clusterA and clusterB) with distinct immunological and prognostic characteristics. First, clusterB, associated with better outcomes, was characterized by a significantly higher pyroptosis-related signature expression, tumor microenvironment prognostic score, and upregulation of immunotherapy checkpoints. A total of 262 differentially expressed genes between the subtypes were further identified and the Ps-score was built using LASSO and COX regression analyses. The external GEO data set demonstrated that cohorts with low Ps-scores consistently had higher expression of pyroptosis-related signatures, immunocyte infiltration levels, and better prognosis. In addition, external immunotherapy and chemotherapy cohorts validated that patients with lower Ps-scores exhibited significant therapeutic response and clinical benefit. Combined with other clinical characteristics, we successfully constructed a nomogram to effectively predict the survival rate of patients with TNBC. Finally, using the scRNA-seq data sets, we validated the landscape of cellular subtypes of TNBC and successfully constructed an miRNA-Ps-score gene interaction network. These findings indicated that the systematic assessment of tumor pyroptosis and identification of Ps-scores has potential clinical implications and facilitates tailoring optimal immunotherapeutic strategies for TNBC.
三阴性乳腺癌（TNBC）由于生物学异质性，预后较差且对免疫治疗反应不佳。迫切需要筛选可靠的指标，尤其是能够预测患者预后的免疫治疗相关生物标志物。细胞焦亡作为一种炎症诱导的程序性细胞死亡类型，已被证明可在多种肿瘤中营造肿瘤抑制环境并改善化疗反应。然而，细胞焦亡在TNBC中的具体治疗效果仍不清楚。在本研究中，我们通过对119例TNBC患者的细胞焦亡相关特征进行共识聚类，将其分为两个具有不同免疫和预后特征的亚型（clusterA和clusterB）。首先，与较好预后相关的clusterB的特征是细胞焦亡相关特征表达显著更高、肿瘤微环境预后评分更高以及免疫治疗检查点上调。进一步鉴定了两个亚型之间总共262个差异表达基因，并使用LASSO和COX回归分析构建了Ps评分。外部GEO数据集表明，低Ps评分的队列始终具有更高的细胞焦亡相关特征表达、免疫细胞浸润水平以及更好的预后。此外，外部免疫治疗和化疗队列验证了低Ps评分的患者表现出显著的治疗反应和临床获益。结合其他临床特征，我们成功构建了一个列线图，以有效预测TNBC患者的生存率。最后，利用单细胞RNA测序数据集，我们验证了TNBC细胞亚型的格局，并成功构建了一个miRNA-Ps评分基因相互作用网络。这些发现表明，对肿瘤细胞焦亡的系统评估和Ps评分的鉴定具有潜在的临床意义，并有助于为TNBC量身定制最佳免疫治疗策略。
