Breast Medical Oncology, Yale Cancer Center, Yale University, New Haven, USA; Department of Oncological Internal Medicine and Clinical Pharmacology "B", National Institute of Oncology, Budapest, Hungary.
Departments of Pathology, Yale School of Medicine, New Haven, USA.
Ann Oncol. 2018 Nov 1;29(11):2232-2239. doi: 10.1093/annonc/mdy399.
Little is known about how the immune microenvironment of breast cancer evolves during disease progression.
We compared tumor infiltrating lymphocyte (TIL) count, programmed death-ligand 1 (PD-L1) protein expression by immunohistochemistry and mRNA levels of 730 immune-related genes using Nanostring technology in primary and metastatic cancer samples.
TIL counts and PD-L1 positivity were significantly lower in metastases. Immune cell metagenes corresponding to CD8, T-helper, T-reg, Cytotoxic T, Dendritic and Mastoid cells, and expression of 13 of 29 immuno-oncology therapeutic targets in clinical development including PD1, PD-L1, and CTLA4 were significantly lower in metastases. There was also coordinated down regulation of chemoattractant ligand/receptor pairs (CCL19/CCR7, CXCL9/CXCR3, IL15/IL15R), interferon regulated genes (STAT1, IRF-1,-4,-7, IFI-27,-35), granzyme/granulysin, MHC class I and immune proteasome (PSMB-8,-9,-10) expression in metastases. Immunotherapy response predictive signatures were also lower. The expression of macrophage markers (CD163, CCL2/CCR2, CSF1/CSFR1, CXCR4/CXCL12), protumorigenic toll-like receptor pathway genes (CD14/TLR-1,-2,-4,-5,-6/MyD88), HLA-E, ecto-nuclease CD73/NT5E and inhibitory complement receptors (CD-59,-55,-46) remained high in metastases and represent potential therapeutic targets.
Metastatic breast cancers are immunologically more inert than the corresponding primary tumors but some immune-oncology targets and macrophage and angiogenesis signatures show preserved expression and suggest therapeutic combinations for clinical testing.
关于乳腺癌的免疫微环境在疾病进展过程中是如何演变的，目前知之甚少。
我们比较了原发和转移性肿瘤样本中肿瘤浸润淋巴细胞（TIL）计数、免疫组织化学检测的程序性死亡配体 1（PD-L1）蛋白表达和使用 Nanostring 技术检测的 730 个免疫相关基因的 mRNA 水平。
转移灶中的 TIL 计数和 PD-L1 阳性率显著降低。与 CD8、辅助性 T 细胞、T 调节细胞、细胞毒性 T 细胞、树突状细胞和肥大细胞相对应的免疫细胞基因簇，以及临床开发中 29 种免疫肿瘤治疗靶点中的 13 种（包括 PD1、PD-L1 和 CTLA4）的表达在转移灶中显著降低。趋化因子配体/受体对（CCL19/CCR7、CXCL9/CXCR3、IL15/IL15R）、干扰素调节基因（STAT1、IRF-1、-4、-7、IFI-27、-35）、颗粒酶/颗粒溶素、MHC Ⅰ类和免疫蛋白酶体（PSMB-8、-9、-10）的表达也存在协调下调。免疫治疗反应预测特征也较低。巨噬细胞标志物（CD163、CCL2/CCR2、CSF1/CSFR1、CXCR4/CXCL12）、促肿瘤生成的 Toll 样受体途径基因（CD14/TLR-1、-2、-4、-5、-6/MyD88）、HLA-E、外切核酸酶 CD73/NT5E 和抑制性补体受体（CD-59、-55、-46）在转移灶中仍然高表达，它们代表潜在的治疗靶点。
转移性乳腺癌的免疫惰性明显高于相应的原发性肿瘤，但一些免疫肿瘤靶点和巨噬细胞及血管生成特征显示出保留的表达，并提示临床检测的治疗组合。
