Multi-Omics Profiling Reveals Distinct Microenvironment Characterization and Suggests Immune Escape Mechanisms of Triple-Negative Breast Cancer
Multi-Omics Profiling Reveals Distinct Microenvironment Characterization and Suggests Immune Escape Mechanisms of Triple-Negative Breast Cancer
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多组学分析揭示了独特的微环境特征并提出了三阴性乳腺癌的免疫逃逸机制
DOI：
10.1158/1078-0432.ccr-18-3524
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发表时间：
2019-08-15
影响因子：
11.5
通讯作者：
Shao, Zhi-Ming
中科院分区：
文献类型：
--
作者：
Xiao, Yi;Ma, Ding;Shao, Zhi-Ming
目的：肿瘤微环境对预后和免疫治疗有着深远的影响。然而，三阴性乳腺癌（TNBC）微环境的景观尚未完全了解。实验设计：使用TNBC的最大原始多组学数据集（n = 386），我们进行了广泛的免疫基因组学分析，以探索TNBC微环境的异质性和预后意义。我们进一步分析了TNBC的潜在免疫逃逸机制。结果如下：将TNBC微环境表型分为三个异质簇：簇1，“免疫沙漠”簇，具有低微环境细胞浸润;簇2，“先天免疫失活”簇，具有静息先天免疫细胞和非免疫基质细胞浸润;和簇3，“免疫发炎”簇，具有丰富的适应性和先天免疫细胞浸润。聚类结果在内部用病理切片验证，在外部用癌症基因组图谱和METABRIC队列验证。微环境集群具有显著的预后功效。在潜在的免疫逃逸机制方面，簇1的特征在于不能吸引免疫细胞，并且MYC扩增与低免疫浸润相关。在簇2中，趋化性但先天免疫失活和低肿瘤抗原负荷可能有助于免疫逃逸，并且PI 3 K-AKT通路中的突变可能与这种效应相关。簇3以免疫检查点分子的高表达为特征。结论：我们的研究代表了TNBC患者个性化免疫治疗的一步。免疫检查点抑制剂可能对“免疫炎症”集群有效，而对于“免疫沙漠”和“先天免疫失活”集群应考虑“冷肿瘤”向“热肿瘤”的转化。
Purpose: The tumor microenvironment has a profound impact on prognosis and immunotherapy. However, the landscape of the triple-negative breast cancer (TNBC) microenvironment has not been fully understood. Experimental Design: Using the largest original multi-omics dataset of TNBC (n = 386), we conducted an extensive immunogenomic analysis to explore the heterogeneity and prognostic significance of the TNBC microenvironment. We further analyzed the potential immune escape mechanisms of TNBC. Results: The TNBC microenvironment phenotypes were classified into three heterogeneous clusters: cluster 1, the “immune-desert” cluster, with low microenvironment cell infiltration; cluster 2, the “innate immune-inactivated” cluster, with resting innate immune cells and nonimmune stromal cells infiltration; and cluster 3, the “immune-inflamed” cluster, with abundant adaptive and innate immune cells infiltration. The clustering result was validated internally with pathologic sections and externally with The Cancer Genome Atlas and METABRIC cohorts. The microenvironment clusters had significant prognostic efficacy. In terms of potential immune escape mechanisms, cluster 1 was characterized by an incapability to attract immune cells, and MYC amplification was correlated with low immune infiltration. In cluster 2, chemotaxis but inactivation of innate immunity and low tumor antigen burden might contribute to immune escape, and mutations in the PI3K-AKT pathway might be correlated with this effect. Cluster 3 featured high expression of immune checkpoint molecules. Conclusions: Our study represents a step toward personalized immunotherapy for patients with TNBC. Immune checkpoint inhibitors might be effective for “immune-inflamed” cluster, and the transformation of “cold tumors” into “hot tumors” should be considered for “immune-desert” and “innate immune-inactivated” clusters.