Abstract
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 (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. 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. 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.
Highlights
Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype, which is defined as no expression of estrogen receptor (ER) and progesterone receptor (PR) and no amplification or overexpression of HER2 [1, 2]
We performed k-means clustering of the triple-negative breast cancer (TNBC) microenvironment phenotypes
Adaptive immune cells and inactivated innate immune cells represented the major proportions in the microenvironments of the three clusters
Summary
Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype, which is defined as no expression of estrogen receptor (ER) and progesterone receptor (PR) and no amplification or overexpression of HER2 [1, 2]. Relapse and lack of therapeutic targets are major problems in TNBC treatment [3, 4]. Recent research has demonstrated that TNBC had higher immunogenicity than other subtypes do, suggesting immunotherapeutic strategies for patients with TNBC [5,6,7,8,9]. Recent clinical trials indicated that immunotherapy, such as immune checkpoint inhibitors (ICIs), showed low efficacy in the whole population of patients with TNBC [10,11,12]. A lack of patient selection based on tumor microenvironment landscapes might be the major reason for these disappointing results. The whole landscape of TNBC microenvironment phenotypes remains unknown.
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