Immunological differences between primary and metastatic breast cancer

被引：256
|
作者：
Szekely, B. [1 ,2 ]
Bossuyt, V. [3 ]
Li, X. [1 ]
Wali, V. B. [1 ]
Patwardhan, G. A. [1 ]
Frederick, C. [1 ]
Silber, A. [1 ]
Park, T. [4 ]
Harigopal, M. [3 ]
Pelekanou, V. [3 ]
Zhang, M. [3 ]
Yan, Q. [1 ]
Rimm, D. L. [3 ]
Bianchini, G. [5 ]
Hatzis, C. [1 ]
Pusztai, L. [1 ]
机构：
[1] Yale Univ, Yale Canc Ctr, Breast Med Oncol, New Haven, CT USA
[2] Natl Inst Oncol, Dept Oncol Internal Med & Clin Pharmacol B, Budapest, Hungary
[3] Yale Sch Med, Dept Pathol, New Haven, CT USA
[4] Yale Sch Med, Dept Surg, New Haven, CT USA
[5] Hosp San Raphael, Dept Breast Med Oncol, Milan, Italy
来源：
ANNALS OF ONCOLOGY | 2018年 / 29卷 / 11期
关键词：
breast cancer; metastasis; immune surveillance; immune therapy; immune escape; TUMOR-INFILTRATING LYMPHOCYTES; PROGNOSTIC VALUE; GENE-EXPRESSION; CHEMOTHERAPY; RECEPTOR; HETEROGENEITY; DOCETAXEL; SUBTYPES;
D O I：
10.1093/annonc/mdy399
中图分类号：
R73 [肿瘤学];
学科分类号：
100214 ;
摘要：
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.
引用
收藏
页码：2232 / 2239
页数：8
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