The diversity and plasticity behind ER+/PR−/HER2− breast cancer have not been widely explored. It is essential to identify heterogeneous microenvironment phenotypes and investigate specific genomic events driving the formation of these phenotypes. Based on the immune-related gene expression profiles of 411 ER+/PR−/HER2− breast cancers in the METABRIC cohort, we used consensus clustering to identify heterogeneous immune subtypes and assessed their reproducibility in an independent meta-cohort including 135 patients collected from GEO database. We further analyzed the differences of cellular and molecular characteristics, and potential immune escape mechanism among immune subtypes. In addition, we constructed a transcriptional trajectory to visualize the distribution of individual patient. Our analysis identified and validated five reproducible immune subtypes with distinct cellular and molecular characteristics, potential immune escape mechanisms, genomic drivers, as well as clinical outcomes. An immune-cold subtype, with the least amount of lymphocyte infiltration, had a poorer prognosis. By contrast, an immune-hot subtype, which demonstrated the highest infiltration of CD8+ T cells, DCs and NK cells, and elevated IFN-γ response, had a comparatively favorable prognosis. Other subtypes showed more diverse gene expression and immune infiltration patterns with distinct clinical outcomes. Finally, our analysis revealed a complex immune landscape consisting of both discrete cluster and continuous spectrum. Overall, this study revealed five heterogeneous immune subtypes among ER+/PR–/HER2− breast cancer, also provided important implications for clinical translations.

中文翻译：

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基于基因组和转录组学景观的 ER 阳性、PR 阴性和 HER2 阴性乳腺癌的新型免疫亚型分类

ER+/PR−/HER2− 乳腺癌背后的多样性和可塑性尚未得到广泛探索。识别异质微环境表型并研究驱动这些表型形成的特定基因组事件至关重要。根据 METABRIC 队列中 411 例 ER+/PR−/HER2− 乳腺癌的免疫相关基因表达谱，我们使用共识聚类来识别异质免疫亚型，并评估其在独立元队列（包括从 GEO 收集的 135 名患者）中的可重复性数据库。我们进一步分析了免疫亚型之间细胞和分子特征的差异以及潜在的免疫逃逸机制。此外，我们构建了转录轨迹来可视化个体患者的分布。我们的分析确定并验证了五种可重复的免疫亚型，它们具有不同的细胞和分子特征、潜在的免疫逃逸机制、基因组驱动因素以及临床结果。淋巴细胞浸润量最少的免疫感冒亚型预后较差。相比之下，免疫热亚型的 CD8+ T 细胞、DC 和 NK 细胞浸润最高，IFN-γ 反应升高，预后相对较好。其他亚型表现出更多样化的基因表达和免疫浸润模式，具有不同的临床结果。最后，我们的分析揭示了由离散簇和连续谱组成的复杂免疫景观。总体而言，这项研究揭示了 ER+/PR–/HER2− 乳腺癌中的五种异质免疫亚型，也为临床转化提供了重要意义。