Establishment of a tumor immune microenvironment-based molecular classification system of breast cancer for immunotherapy.
Establishment of a tumor immune microenvironment-based molecular classification system of breast cancer for immunotherapy.
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建立基于肿瘤免疫微环境的乳腺癌免疫治疗分子分类系统。
DOI：
10.18632/aging.203682
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发表时间：
2021-11-11
期刊：
影响因子：
--
通讯作者：
Xu M
中科院分区：
文献类型：
--
作者：
Zheng X;Li L;Yu C;Yang J;Zhao Y;Su C;Yu J;Xu M
抗肿瘤免疫疗法可以在其临床应用后实现有希望和持久的反应。然而，肿瘤免疫微环境的异质性导致个体反应率的差异。在这项研究中，我们确定了新的免疫相关的乳腺癌分子亚类使用非负矩阵分解分析。我们招募了4184名乳腺癌患者，其中包括来自癌症基因组图谱的1104名患者作为训练队列，来自另外四个独立数据集的3080名患者作为验证队列。在训练队列中，36.9%的患者表现出显著较高的免疫细胞浸润和免疫应答相关特征的富集，被归类为免疫类，这通过探测免疫细胞标志物（CD 3，CD 19和CD 163）的表达来证实。在免疫类别中，53.3%的患者属于免疫抑制亚类，其特征在于基质相关特征和免疫抑制细胞的激活。免疫类别中的其余患者被分配到免疫激活亚类。免疫激活亚类中干扰素-γ和颗粒酶B水平较高，而免疫抑制亚类中转化生长因子-β1和程序性细胞死亡-1（PD-1）水平较高。在验证队列中概括了已建立的分子分类系统。预测免疫激活的亚类对抗PD-1免疫疗法具有更好的应答。免疫相关亚类与拷贝数改变、肿瘤突变负荷、新抗原、肿瘤浸润淋巴细胞富集、PD-1/程序性死亡配体1表达、突变景观和各种浸润免疫细胞的差异相关。总体而言，我们建立了一种新的乳腺癌免疫相关分子分类，可用于选择免疫治疗的候选患者。
Antitumor immunotherapy can enable promising and durable responses following their clinical application. However, heterogeneity in the tumor immune microenvironment leads to differences in the individual response rates. In this study, we identified novel immune-related molecular subclasses of breast cancer using a non-negative matrix factorization analysis. We enrolled 4184 patients with breast cancer, including 1104 patients from The Cancer Genome Atlas as a training cohort and 3080 patients from another four independent datasets as validation cohorts. In the training cohort, 36.9% of patients who exhibited significantly higher immunocyte infiltration and enrichment of immune response-associated signatures were categorized into an immune class, which was confirmed by probing the expression of immunocyte markers (CD3, CD19, and CD163). Within the immune class, 53.3% of patients belonged to an immune-suppressed subclass, characterized by the activation of stroma-related signatures and immune-suppressive cells. The remaining patients in the immune class were allocated to an immune-activated subclass. The interferon-γ and granzyme B levels were higher in the immune-activated subclass, whereas the transforming growth factor-β1 and programmed cell death-1 (PD-1) levels were higher in the immune-suppressed subclass. The established molecular classification system was recapitulated in validation cohorts. The immune-activated subclass was predicted to have a better response to anti-PD-1 immunotherapy. The immune-related subclasses were associated with differences in copy number alterations, tumor mutation burden, neoantigens, tumor-infiltrating lymphocyte enrichment, PD-1/programmed death-ligand 1 expression, mutation landscape, and various infiltration immunocytes. Overall, we established a novel immune-related molecular classification of breast cancer, which may be used to select candidate patients for immunotherapy.
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