Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.
State Key Laboratory of Genetic Engineering, School of Life Sciences and Human Phenome Institute, Fudan University, Shanghai, China.
Clin Cancer Res. 2019 Aug 15;25(16):5002-5014. doi: 10.1158/1078-0432.CCR-18-3524. Epub 2019 Mar 5.
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.
Using the largest original multi-omics dataset of TNBC ( = 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.
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 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.
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.
肿瘤微环境对预后和免疫治疗有深远影响。然而，三阴性乳腺癌（TNBC）微环境的全貌尚未完全了解。
使用最大的 TNBC 原始多组学数据集（=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。
TNBC 微环境表型分为三个异质簇：簇 1 为“免疫荒漠”簇，微环境细胞浸润低；簇 2 为“先天免疫失活”簇，存在静止的先天免疫细胞和非免疫基质细胞浸润；簇 3 为“免疫炎症”簇，富含适应性和先天免疫细胞浸润。聚类结果通过病理切片进行内部验证，并与 The Cancer Genome Atlas 和 METABRIC 队列进行外部验证。微环境聚类具有显著的预后效果。就潜在的免疫逃逸机制而言，簇 1 的特征是无法吸引免疫细胞，扩增与免疫浸润低相关。簇 2 中，趋化作用但先天免疫失活和低肿瘤抗原负荷可能导致免疫逃逸，PI3K-AKT 通路的突变可能与此相关。簇 3 表现出免疫检查点分子的高表达。
我们的研究代表了为 TNBC 患者实现个体化免疫治疗的一步。免疫检查点抑制剂可能对“免疫炎症”簇有效，对于“免疫荒漠”和“先天免疫失活”簇，应考虑将“冷肿瘤”转化为“热肿瘤”。
