Ju Gaoda, Zeng Kai, Lu Linlin, Diao Han, Wang Hao, Li Xiaomin, Zhou Tianhao
Department of Medical Oncology, Key Laboratory of Carcinogenesis & Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute Beijing 100142, China.
Department of Thyroid Surgery, The Eighth Affiliated Hospital, Sun Yat-sen University Shenzhen 518000, Guangdong, China.
Am J Cancer Res. 2023 Feb 15;13(2):569-588. eCollection 2023.
Patients with triple-negative breast cancer (TNBC) reportedly benefit from immune checkpoint blockade (ICB) therapy. However, the subtype-specific vulnerabilities of ICB in TNBC remain unclear. As the complex interplay between cellular senescence and anti-tumor immunity has been previously discussed, we aimed to identify markers related to cellular senescence that may serve as potential predictors of response to ICB in TNBC. We used three transcriptomic datasets derived from ICB-treated breast cancer samples at both scRNA-seq and bulk-RNA-seq levels to define the subtype-specific vulnerabilities of ICB in TNBC. Differences in the molecular features and immune cell infiltration among the different TNBC subtypes were further explored using two scRNA-seq, three bulk-RNA-seq, and two proteomic datasets. 18 TNBC samples were collected and utilized to verify the association between gene expression and immune cell infiltration by multiplex immunohistochemistry (mIHC). A specific type of cellular senescence was found to be significantly associated with response to ICB in TNBC. We employed the expression of four senescence-related genes, namely , and , to define a distinct senescence-related classifier using the non-negative matrix factorization approach. Two clusters were identified, namely the senescence-enriching cluster (C1; ) and proliferating-enriching cluster (C2; ). Our results indicated that the C1 cluster responds better to ICB and behaves with higher CD8 T cell infiltration than the C2 cluster. Altogether, in this study, we developed a robust cellular senescence-related classifier of TNBC based on the expression of , and . This classifier act as a potential predictor of clinical outcomes and response to ICB.
据报道，三阴性乳腺癌（TNBC）患者可从免疫检查点阻断（ICB）治疗中获益。然而，ICB在TNBC中的亚型特异性脆弱性仍不清楚。由于先前已讨论过细胞衰老与抗肿瘤免疫之间的复杂相互作用，我们旨在识别与细胞衰老相关的标志物，这些标志物可能作为TNBC中ICB反应的潜在预测指标。我们使用了三个转录组数据集，这些数据集来自ICB治疗的乳腺癌样本的单细胞RNA测序（scRNA-seq）和批量RNA测序（bulk-RNA-seq）水平，以定义ICB在TNBC中的亚型特异性脆弱性。使用两个scRNA-seq、三个bulk-RNA-seq和两个蛋白质组数据集，进一步探索了不同TNBC亚型之间分子特征和免疫细胞浸润的差异。收集了18个TNBC样本，并通过多重免疫组织化学（mIHC）来验证基因表达与免疫细胞浸润之间的关联。发现一种特定类型的细胞衰老与TNBC中ICB的反应显著相关。我们利用四个衰老相关基因（即 、 、 和 ）的表达，采用非负矩阵分解方法定义了一个独特的衰老相关分类器。识别出两个簇，即衰老富集簇（C1； ）和增殖富集簇（C2； ）。我们的结果表明，C1簇对ICB的反应更好，并且与C2簇相比，其CD8 T细胞浸润更高。总之，在本研究中，我们基于 、 和 的表达，开发了一种强大的TNBC细胞衰老相关分类器。该分类器可作为临床结果和ICB反应的潜在预测指标。
