Abstract P4-06-24: Microenvironment heterogeneity of triple-negative breast cancer reveals distinct immune escape mechanisms and potential driver events

Yi Xiao, D. Ma, Shimin Zhao, Y-Z Jiang, Z. Shao
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Abstract

Background The microenvironment phenotypes strongly affect the immunotherapeutic strategies for triple-negative breast cancer (TNBC). Although the multi-omics profile of TNBC has been comprehensively characterized, few studies have focused on the microenvironment phenotypes of TNBC. Methods With multi-omics data for the largest single-center TNBC cohort (n=386), we first established a TNBC-specific microenvironment cell signature. We further used single sample gene set enrichment analysis to calculate the relative number of microenvironment cell subsets in each sample. Then, we performed k-means clustering to classify the TNBC microenvironment phenotypes into heterogeneous clusters. Furthermore, we systematically analyzed the extrinsic and intrinsic immune escape mechanisms of different TNBC microenvironment clusters. In addition, we explored genomic alterations that might decrease immune infiltration in certain TNBC microenvironment clusters. Results We classified the TNBC microenvironment phenotypes into three heterogeneous clusters. Cluster 1 (type 1 “cold tumor”) had low microenvironment cells infiltration. Cluster 2 (type 2 “cold tumor”) was characterized by resting innate immune cells, fibroblasts and endothelial cells infiltration. Cluster 3 (“hot tumor”) was featured by adaptive immune cells infiltration. Analysis of immune escape mechanism revealed that an incapability to attract innate immune cells (resulting in failure of adaptive immunity) led to immune escape of cluster 1. The chemotaxis but inactivation of innate immunity (also leading to failure of adaptive immunity) and low tumor antigen burden resulted in immune escape of cluster 2. High expression of immune checkpoint molecules contributed to immune escape of cluster 3. In addition, we found that tumor infiltrating lymphocytes (TILs) were positively correlated with immune checkpoint molecules expression, while mutation load was negatively correlated with those indicators in triple-negative breast cancer. Analysis of enrichment pathways, mutations and somatic copy number variations between the “cold tumor” and “hot tumor” clusters revealed that amplification of MYC and activation of MYC-related pathways might decrease the immune infiltration of cluster 1. Mutations in PI3K-AKT pathway members and activation of fibroblasts-related pathways might decrease the immune infiltration of cluster 2. Conclusion Utilizing the largest single-center TNBC cohort with multi-omics data, our study first revealed the heterogeneity of the TNBC microenvironment, with translational significance both clinically and biologically. First, we identified a subtype of “hot tumor” in TNBC (cluster 3), for which immune checkpoint blockers (ICBs) might be effective. TILs and immune checkpoint molecules expression but not mutation load might predict the efficacy of ICBs. Second, we presumed some genomic alterations that might drive “cold tumor” formation in TNBC. Our study represents a step toward personalized immunotherapy for TNBC patients. Key Words triple-negative breast cancer, multi-omics, microenvironment heterogeneity, immune escape Citation Format: Xiao Y, Ma D, Zhao S, Jiang Y-Z, Shao Z-M. Microenvironment heterogeneity of triple-negative breast cancer reveals distinct immune escape mechanisms and potential driver events [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P4-06-24.
P4-06-24:三阴性乳腺癌的微环境异质性揭示了不同的免疫逃逸机制和潜在的驱动事件
微环境表型强烈影响三阴性乳腺癌(TNBC)的免疫治疗策略。虽然TNBC的多组学特征已经被全面表征,但很少有研究关注TNBC的微环境表型。方法利用最大的单中心TNBC队列(n=386)的多组学数据,我们首先建立了TNBC特异性微环境细胞特征。我们进一步使用单样本基因集富集分析来计算每个样本中微环境细胞亚群的相对数量。然后,我们进行k-means聚类,将TNBC微环境表型分类为异质集群。此外,我们系统地分析了不同TNBC微环境集群的外在和内在免疫逃逸机制。此外,我们探索了基因组改变可能会降低某些TNBC微环境集群的免疫浸润。结果将TNBC微环境表型分为3个异质集群。簇1(1型“冷瘤”)微环境细胞浸润低。簇2(2型“冷肿瘤”)的特征是静止的先天免疫细胞、成纤维细胞和内皮细胞浸润。集群3(“热瘤”)以适应性免疫细胞浸润为特征。免疫逃逸机制分析表明,簇1的免疫逃逸是由于无法吸引先天免疫细胞(导致适应性免疫失败)。先天免疫趋化但失活(也导致适应性免疫失败)和肿瘤抗原负荷低导致簇2免疫逃逸。免疫检查点分子的高表达促进了簇3的免疫逃逸。此外,我们发现在三阴性乳腺癌中,肿瘤浸润淋巴细胞(tumor浸润淋巴细胞,til)与免疫检查点分子表达呈正相关,而突变负荷与这些指标呈负相关。对“冷瘤”和“热瘤”簇间富集途径、突变和体细胞拷贝数变化的分析表明,MYC的扩增和MYC相关途径的激活可能会降低簇1的免疫浸润。PI3K-AKT通路成员的突变和成纤维细胞相关通路的激活可能会降低簇2的免疫浸润。利用最大的单中心TNBC队列和多组学数据,我们的研究首次揭示了TNBC微环境的异质性,具有临床和生物学的翻译意义。首先,我们在TNBC(簇3)中发现了一种“热肿瘤”亚型,免疫检查点阻滞剂(ICBs)可能对其有效。TILs和免疫检查点分子的表达而不是突变负荷可能预测ICBs的疗效。其次,我们假设一些基因组改变可能驱动TNBC中“冷肿瘤”的形成。我们的研究为TNBC患者的个性化免疫治疗迈出了一步。关键词:三阴性乳腺癌,多组学,微环境异质性,免疫逃逸三阴性乳腺癌的微环境异质性揭示了不同的免疫逃逸机制和潜在的驱动事件[摘要]。2018年圣安东尼奥乳腺癌研讨会论文集;2018年12月4-8日;费城(PA): AACR;中国癌症杂志,2019;79(4增刊):P4-06-24。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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