Unraveling Triple-Negative Breast Cancer Tumor Microenvironment Heterogeneity: Towards an Optimized Treatment Approach
Unraveling Triple-Negative Breast Cancer Tumor Microenvironment Heterogeneity: Towards an Optimized Treatment Approach
复制标题
揭开三阴性乳腺癌微环境的异质性：朝着优化的治疗方法迈进
DOI：
10.1093/jnci/djz208
复制
发表时间：
2020-07-01
影响因子：
10.3
通讯作者：
Sotiriou, Christos
中科院分区：
文献类型：
--
作者：
Bareche, Yacine;Buisseret, Laurence;Sotiriou, Christos
背景：最近的基因表达谱分析发现了至少四种不同的三阴性乳腺癌（TNBC）分子亚型。然而，人们对它们的肿瘤微环境 (TME) 异质性知之甚少。 方法：在这里，我们使用来自大型 TNBC 系列总计 1512 个样本的公开转录组和基因组数据集，研究了每种 TNBC 分子亚型内的 TME 异质性，包括免疫浸润定位和组成以及可靶向免疫途径的表达。使用逻辑回归模型评估分子亚型和特定特征之间的关联。所有统计检验都是双向的。结果：我们证明每种 TNBC 分子亚型都表现出与特定免疫、血管化、基质和代谢生物学过程以及特定免疫组成和定位相关的不同 TME 特征。免疫调节亚型与适应性免疫相关基因特征的最高表达和完全发炎的空间模式相关，似乎是免疫检查点抑制剂的最佳候选者。相比之下，大多数间充质干细胞样和管腔雄激素受体肿瘤表现出免疫抑制表型，基质特征的高表达水平证明了这一点。基底样、管腔雄激素受体和间充质亚型表现出与基质和代谢 TME 特征相关的免疫冷表型，并在边缘限制的空间模式中丰富。染色体高度不稳定性和染色体 5q 和 15q 区域拷贝数丢失（包括主要组织相容性复合体相关基因的基因组丢失）的肿瘤显示出细胞毒活性降低，这是一种看似合理的免疫逃逸机制。结论：我们的结果表明，每种 TNBC 亚型都与特定的 TME 谱相关，为 TNBC 患者免疫治疗的合理定制奠定了基础。
Background: Recent efforts of gene expression profiling analyses recognized at least four different triple-negative breast cancer (TNBC) molecular subtypes. However, little is known regarding their tumor microenvironment (TME) heterogeneity.Methods: Here, we investigated TME heterogeneity within each TNBC molecular subtype, including immune infiltrate localization and composition together with expression of targetable immune pathways, using publicly available transcriptomic and genomic datasets from a large TNBC series totaling 1512 samples. Associations between molecular subtypes and specific features were assessed using logistic regression models. All statistical tests were two-sided.Results: We demonstrated that each TNBC molecular subtype exhibits distinct TME profiles associated with specific immune, vascularization, stroma, and metabolismbiological processes together with specific immune composition and localization. The immunomodulatory subtype was associated with the highest expression of adaptive immune-related gene signatures and a fully inflamed spatial pattern appearing to be the optimal candidate for immune check point inhibitors. In contrast, most mesenchymal stem-like and luminal androgen receptor tumors showed an immunosuppressive phenotype as witnessed by high expression levels of stromal signatures. Basal-like, luminal androgen receptor, and mesenchymal subtypes exhibited an immune cold phenotype associated with stromal and metabolism TME signatures and enriched in margin-restricted spatial pattern. Tumors with high chromosomal instability and copy number loss in the chromosome 5q and 15q regions, including genomic loss of major histocompatibility complex related genes, showed reduced cytotoxic activity as a plausible immune escape mechanism.Conclusions: Our results demonstrate that each TNBC subtype is associated with specific TME profiles, setting the ground for a rationale tailoring of immunotherapy in TNBC patients.