O'Meara Tess, Marczyk Michal, Qing Tao, Yaghoobi Vesal, Blenman Kim, Cole Kimberly, Pelekanou Vasiliki, Rimm David L, Pusztai Lajos
Department of Medical Oncology, Yale School of Medicine, New Haven, CT.
Data Mining Division, Silesian University of Technology, Gliwice, Poland.
JCO Precis Oncol. 2020 Jun 26;4. doi: 10.1200/PO.19.00350. eCollection 2020.
A subset of estrogen receptor-positive (ER-positive) breast cancer (BC) contains high levels of tumor-infiltrating lymphocytes (TILs), similar to triple-negative BC (TNBC). The majority of immuno-oncology trials target TNBCs because of the greater proportion of TIL-rich TNBCs. The extent to which the immune microenvironments of immune-rich ER-positive BC and TNBC differ is unknown.
RNA sequencing data from The Cancer Genome Atlas (TCGA; n = 697 ER-positive BCs; n = 191 TNBCs) were used for discovery; microarray expression data from Molecular Taxonomy of Breast Cancer International Consortium (METABRIC; n = 1,186 ER-positive BCs; n = 297 TNBCs) was used for validation. Patients in the top 25th percentile of a previously published total TIL metagene score distribution were considered immune rich. We compared expression of immune cell markers, immune function metagenes, and immuno-oncology therapeutic targets among immune-rich subtypes.
Relative fractions of resting mast cells (TCGA = .009; METABRIC = 4.09E-15), CD8 T cells (TCGA = .015; METABRIC = 0.390), and M2-like macrophages (TCGA = 4.68E-05; METABRIC = .435) were higher in immune-rich ER-positive BCs, but M0-like macrophages (TCGA = 0.015; METABRIC = .004) and M1-like macrophages (TCGA = 9.39E-08; METABRIC = 6.24E-11) were higher in immune-rich TNBCs. Ninety-one immune-related genes (eg, , , , , ) and a transforming growth factor β (TGF-β) response metagene were significantly overexpressed in immune-rich ER-positive BCs, whereas 41 immune-related genes (eg, , , , ) were overexpressed in immune-rich TNBCs in both discovery and validation data sets. TGF-β pathway member genes correlated negatively with expression of immune activation markers (, granzyme-B, perforin) and positively with M2-like macrophages (, , and and regulatory T-cell () markers in both subtypes.
Different immunotherapy strategies may be optimal in immune-rich ER-positive BC and TNBC. Drugs targeting the TGF-β pathway and M2-like macrophages are promising strategies in immune-rich ER-positive BCs to augment antitumor immunity.
一部分雌激素受体阳性（ER阳性）乳腺癌（BC）含有高水平的肿瘤浸润淋巴细胞（TIL），类似于三阴性乳腺癌（TNBC）。由于富含TIL的TNBC比例更高，大多数免疫肿瘤学试验都以TNBC为靶点。富含免疫细胞的ER阳性BC和TNBC的免疫微环境差异程度尚不清楚。
使用来自癌症基因组图谱（TCGA；n = 697例ER阳性BC；n = 191例TNBC）的RNA测序数据进行发现；使用来自国际乳腺癌分子分类联盟（METABRIC；n = 1186例ER阳性BC；n = 297例TNBC）的微阵列表达数据进行验证。先前发表的总TIL元基因评分分布中处于第25百分位数以上的患者被认为富含免疫细胞。我们比较了富含免疫细胞的亚型之间免疫细胞标志物、免疫功能元基因和免疫肿瘤学治疗靶点的表达。
在富含免疫细胞的ER阳性BC中，静息肥大细胞（TCGA = 0.009；METABRIC = 4.09E - 15）、CD8 T细胞（TCGA = 0.015；METABRIC = 0.390）和M2样巨噬细胞（TCGA = 4.68E - 05；METABRIC = 0.435）的相对比例更高，但在富含免疫细胞的TNBC中，M0样巨噬细胞（TCGA = 0.015；METABRIC = 0.004）和M1样巨噬细胞（TCGA = 9.39E - 08；METABRIC = 6.24E - 11）的比例更高。91个免疫相关基因（如……）和一个转化生长因子β（TGF-β）反应元基因在富含免疫细胞的ER阳性BC中显著过表达，而在发现和验证数据集中，41个免疫相关基因（如……）在富含免疫细胞的TNBC中过表达。在两种亚型中，TGF-β信号通路成员基因与免疫激活标志物（如颗粒酶B、穿孔素）的表达呈负相关，与M2样巨噬细胞（如……）以及调节性T细胞（……）标志物呈正相关。
在富含免疫细胞的ER阳性BC和TNBC中，不同的免疫治疗策略可能是最优的。靶向TGF-β信号通路和M2样巨噬细胞的药物是增强富含免疫细胞的ER阳性BC抗肿瘤免疫力的有前景的策略。
