Dual roles for immune metagenes in breast cancer prognosis and therapy prediction.
Dual roles for immune metagenes in breast cancer prognosis and therapy prediction.
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DOI：
10.1186/s13073-014-0080-8
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发表时间：
2014
期刊：
影响因子：
12.3
通讯作者：
Miller LD
中科院分区：
文献类型：
--
作者：
Alistar A;Chou JW;Nagalla S;Black MA;D'Agostino R Jr;Miller LD
乳腺癌的新辅助化疗导致临床反应的相当大的差异，只有10 - 20%的病例实现完全的病理反应（pCR）。决定pCR程度的生物学和临床因素尚不完全清楚。越来越多的证据表明，患者的免疫系统有助于肿瘤的消退，并且可以通过治疗来调节。最常观察到这种关联的细胞类型是效应肿瘤浸润淋巴细胞（til），如细胞毒性T细胞、自然杀伤细胞和B细胞。我们和其他人已经证明，乳腺癌中TILs的相对丰度可以通过肿瘤内协调表达的免疫细胞特异性基因的转录水平来量化。通过表达微阵列分析，我们最近发现了三个免疫基因特征，或宏基因，它们似乎反映了不同肿瘤浸润白细胞群的相对丰度。B/P （B细胞/浆细胞）、T/NK （T细胞/自然杀伤细胞）和M/D（单核细胞/树突状细胞）免疫meta与基底样、her2富集和腔内B固有亚型高增殖癌患者的无远处转移生存率显著相关。鉴于组织病理学证据表明TIL丰度可以预测新辅助治疗的疗效，我们评估了预后免疫宏细胞的治疗预测潜力。我们假设化疗前免疫基因特征可以显著预测肿瘤反应。在一项针对701名接受新辅助化疗的乳腺癌患者的多机构荟萃队列分析中，通过logistic回归研究了肿瘤活检的基因表达谱，以确定免疫宏基因、肿瘤增殖能力和内在亚型之间是否存在治疗预测性相互作用。单因素分析表明，B/P、T/NK和M/D元基因均与良好的病理反应呈显著正相关。在多变量分析中，增殖能力和内在亚型以不同的方式改变免疫宏宏的意义，在调整其他变量后，M/D和B/P宏宏的总体意义最大。浸润性免疫细胞的基因表达特征具有预后和治疗预测价值，受肿瘤增殖能力和内在亚型的影响。血浆B细胞和髓源性抗原呈递细胞的抗肿瘤功能可能解释了新辅助化疗病理反应的变异性。本文的在线版本（doi:10.1186/ s130773 -014-0080-8）包含补充材料，授权用户可使用。
Neoadjuvant chemotherapy for breast cancer leads to considerable variability in clinical responses, with only 10 to 20% of cases achieving complete pathologic responses (pCR). Biological and clinical factors that determine the extent of pCR are incompletely understood. Mounting evidence indicates that the patient’s immune system contributes to tumor regression and can be modulated by therapies. The cell types most frequently observed with this association are effector tumor infiltrating lymphocytes (TILs), such as cytotoxic T cells, natural killer cells and B cells. We and others have shown that the relative abundance of TILs in breast cancer can be quantified by intratumoral transcript levels of coordinately expressed, immune cell-specific genes. Through expression microarray analysis, we recently discovered three immune gene signatures, or metagenes, that appear to reflect the relative abundance of distinct tumor-infiltrating leukocyte populations. The B/P (B cell/plasma cell), T/NK (T cell/natural killer cell) and M/D (monocyte/dendritic cell) immune metagenes were significantly associated with distant metastasis-free survival of patients with highly proliferative cancer of the basal-like, HER2-enriched and luminal B intrinsic subtypes. Given the histopathological evidence that TIL abundance is predictive of neoadjuvant treatment efficacy, we evaluated the therapy-predictive potential of the prognostic immune metagenes. We hypothesized that pre-chemotherapy immune gene signatures would be significantly predictive of tumor response. In a multi-institutional, meta-cohort analysis of 701 breast cancer patients receiving neoadjuvant chemotherapy, gene expression profiles of tumor biopsies were investigated by logistic regression to determine the existence of therapy-predictive interactions between the immune metagenes, tumor proliferative capacity, and intrinsic subtypes. By univariate analysis, the B/P, T/NK and M/D metagenes were all significantly and positively associated with favorable pathologic responses. In multivariate analyses, proliferative capacity and intrinsic subtype altered the significance of the immune metagenes in different ways, with the M/D and B/P metagenes achieving the greatest overall significance after adjustment for other variables. Gene expression signatures of infiltrating immune cells carry both prognostic and therapy-predictive value that is impacted by tumor proliferative capacity and intrinsic subtype. Anti-tumor functions of plasma B cells and myeloid-derived antigen-presenting cells may explain more variability in pathologic response to neoadjuvant chemotherapy than previously recognized. The online version of this article (doi:10.1186/s13073-014-0080-8) contains supplementary material, which is available to authorized users.
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DOI：
10.1001/jama.2011.593
发表时间：
2011-05-11
期刊：
JAMA
影响因子：
--
作者：
Hatzis C;Pusztai L;Valero V;Booser DJ;Esserman L;Lluch A;Vidaurre T;Holmes F;Souchon E;Wang H;Martin M;Cotrina J;Gomez H;Hubbard R;Chacón JI;Ferrer-Lozano J;Dyer R;Buxton M;Gong Y;Wu Y;Ibrahim N;Andreopoulou E;Ueno NT;Hunt K;Yang W;Nazario A;DeMichele A;O'Shaughnessy J;Hortobagyi GN;Symmans WF
通讯作者：
Symmans WF
DOI：
10.1093/jnci/djn309
发表时间：
2008-10-01
期刊：
Journal of the National Cancer Institute
影响因子：
--
作者：
Ellis MJ;Tao Y;Luo J;A'Hern R;Evans DB;Bhatnagar AS;Chaudri Ross HA;von Kameke A;Miller WR;Smith I;Eiermann W;Dowsett M
通讯作者：
Dowsett M
影响因子：
3.8
作者：
Ascierto, Maria Libera;Kmieciak, Maciej;Idowu, Michael O.;Manjili, Rose;Zhao, Yingdong;Grimes, Margaret;Dumur, Catherine;Wang, Ena;Ramakrishnan, Viswanathan;Wang, Xiang-Yang;Bear, Harry D.;Marincola, Francesco M.;Manjili, Masoud H.
通讯作者：
Manjili, Masoud H.
DOI：
10.4049/jimmunol.1301966
发表时间：
2013-11-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Griesinger AM;Birks DK;Donson AM;Amani V;Hoffman LM;Waziri A;Wang M;Handler MH;Foreman NK
通讯作者：
Foreman NK
DOI：
10.1084/jem.20050915
发表时间：
2005-12-19
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Casares N;Pequignot MO;Tesniere A;Ghiringhelli F;Roux S;Chaput N;Schmitt E;Hamai A;Hervas-Stubbs S;Obeid M;Coutant F;Métivier D;Pichard E;Aucouturier P;Pierron G;Garrido C;Zitvogel L;Kroemer G
通讯作者：
Kroemer G