Bluewater Biotech LLC, PO Box 1010, New Providence, NJ, 07974, USA.
Laboratory of Clinical and Experimental Pathology, CHU Nice, FHU OncoAge, University Côte d'Azur, 06100, Nice, France.
Cell Oncol (Dordr). 2022 Jun;45(3):463-477. doi: 10.1007/s13402-022-00677-6. Epub 2022 May 11.
Reliable biomarkers to predict the outcome and treatment response of estrogen receptor (ER)-negative breast cancer (BC) are urgently needed. Since immune-related signaling plays an important role in the tumorigenesis of ER-negative BC, we asked whether Notch genes, alone or in combination with other immune genes, can be used to predict the clinical outcome and immune checkpoint blockade (ICB) for this type of cancer.
We analyzed transcriptome data of 6918 BC samples from five independent cohorts, 81 xenograft triple-negative BC tumors that respond differently to ICB treatment and 754 samples of different cancer types from patients treated with ICB agents.
We found that among four Notch genes, the expression levels of NOTCH1 and NOTCH4 were positively associated with recurrence of ER-negative BC, and that combined expression of these two genes (named Notch14) further enhanced this association, which was comparable with that of the Notch pathway signature. Analysis of 1182 immune-related genes revealed that the expression levels of most HLA genes, particularly HLA-DMA and -DRA, were reversely associated with recurrence in ER-negative BC with low, but not high Notch14 expression. A combined expression signature of NOTCH1, NOTCH4, HLA-DMA and HLA-DRA was more prognostic for ER-negative and triple-negative BCs than previously reported immune-related signatures. Furthermore, we found that the expression levels of these four genes were also synergistically associated with T cell exclusion score, infiltration of specific T cells and ICB efficacy in ER-negative BC, thereby providing a potential molecular mechanism for the synergistic effect of these genes on BC.
Our data indicate that a gene signature composed of NOTCH1, NOTCH4, HLA-DMA and HLA-DRA may serve as a potential promising biomarker for predicting ICB therapy efficacy and recurrence in ER-negative/triple-negative BCs.
迫切需要可靠的生物标志物来预测雌激素受体（ER）阴性乳腺癌（BC）的预后和治疗反应。由于免疫相关信号在 ER 阴性 BC 的肿瘤发生中起着重要作用，我们想知道 Notch 基因，单独或与其他免疫基因结合，是否可以用于预测此类癌症的临床结果和免疫检查点阻断（ICB）。
我们分析了来自五个独立队列的 6918 例 BC 样本的转录组数据、81 例对 ICB 治疗反应不同的异种移植三阴性 BC 肿瘤以及 754 例接受 ICB 药物治疗的不同癌症类型的样本。
我们发现，在四个 Notch 基因中，NOTCH1 和 NOTCH4 的表达水平与 ER 阴性 BC 的复发呈正相关，并且这两个基因的联合表达（命名为 Notch14）进一步增强了这种相关性，与 Notch 通路特征相当。对 1182 个免疫相关基因的分析表明，大多数 HLA 基因的表达水平，特别是 HLA-DMA 和 -DRA，与低表达但高 Notch14 表达的 ER 阴性 BC 的复发呈负相关。NOTCH1、NOTCH4、HLA-DMA 和 HLA-DRA 的联合表达特征比以前报道的免疫相关特征更能预测 ER 阴性和三阴性 BC。此外，我们发现这四个基因的表达水平也与 T 细胞排斥评分、特定 T 细胞浸润和 ER 阴性 BC 的 ICB 疗效呈协同相关，从而为这些基因对 BC 的协同作用提供了潜在的分子机制。
我们的数据表明，由 NOTCH1、NOTCH4、HLA-DMA 和 HLA-DRA 组成的基因特征可能成为预测 ER 阴性/三阴性 BC 的 ICB 治疗疗效和复发的潜在有前途的生物标志物。
