Spatial organization of dendritic cells within tumor draining lymph nodes impacts clinical outcome in breast cancer patients

被引：38

作者：

Chang, Andrew Y. ^{[1
]}

Bhattacharya, Nupur ^{[1
]}

Mu, Jian ^{[2
]}

Setiadi, A. Francesca ^{[1
]}

Carcamo-Cavazos, Valeria ^{[1
]}

Lee, Gerald H. ^{[1
]}

Simons, Diana L. ^{[1
,7
,8
]}

Yadegarynia, Sina ^{[1
]}

Hemati, Kaveh ^{[1
]}

Kapelner, Adam ^{[3
]}

Ming, Zheng ^{[4
]}

Krag, David N. ^{[5
]}

Schwartz, Erich J. ^{[6
]}

Chen, Danny Z. ^{[2
]}

Lee, Peter P. ^{[1
,7
,8
]}

机构：

[1] Stanford Univ, Dept Med, Stanford, CA 94305 USA

[2] Univ Notre Dame, Dept Comp Sci & Engn, Notre Dame, IN 46556 USA

[3] Univ Penn, Wharton Sch, Dept Stat, Philadelphia, PA 19104 USA

[4] Stanford Univ, Sch Med, Dept Anesthesia, Stanford, CA 94305 USA

[5] Univ Vermont, Coll Med, Burlington, VT 05405 USA

[6] Stanford Univ, Dept Pathol, Stanford, CA 94305 USA

[7] City Hope Natl Med Ctr, Canc Immunotherapeut & Tumor Immunol, Duarte, CA 91010 USA

[8] City Hope Natl Med Ctr, Beckman Res Inst, Duarte, CA 91010 USA

来源：

JOURNAL OF TRANSLATIONAL MEDICINE | 2013年 / 11卷

基金：

美国国家科学基金会;

关键词：

Breast cancer; Immune cells; Dendritic cells; Clustering; Spatial organization; Lymph nodes; DENDRITIC/LANGERHANS CELLS; MATURATION; DENSITY; ADENOCARCINOMAS; ACTIVATION; CD1A; CD83;

D O I：

10.1186/1479-5876-11-242

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

1001 ;

摘要：

Background: Dendritic cells (DCs) are important mediators of anti-tumor immune responses. We hypothesized that an in-depth analysis of dendritic cells and their spatial relationships to each other as well as to other immune cells within tumor draining lymph nodes (TDLNs) could provide a better understanding of immune function and dysregulation in cancer. Methods: We analyzed immune cells within TDLNs from 59 breast cancer patients with at least 5 years of clinical follow-up using immunohistochemical staining with a novel quantitative image analysis system. We developed algorithms to analyze spatial distribution patterns of immune cells in cancer versus healthy intra-mammary lymph nodes (HLNs) to derive information about possible mechanisms underlying immune-dysregulation in breast cancer. We used the non-parametric Mann-Whitney test for inter-group comparisons, Wilcoxon Matched-Pairs Signed Ranks test for intra-group comparisons and log-rank (Mantel-Cox) test for Kaplan Maier analyses. Results: Degree of clustering of DCs (in terms of spatial proximity of the cells to each other) was reduced in TDLNs compared to HLNs. While there were more numerous DC clusters in TDLNs compared to HLNs, DC clusters within TDLNs tended to have fewer member DCs and also consisted of fewer cells displaying the DC maturity marker CD83. The average number of T cells within a standardized radius of a clustered DC was increased compared to that of an unclustered DC, suggesting that DC clustering was associated with T cell interaction. Furthermore, the number of T cells within the radius of a clustered DC was reduced in tumor-positive TDLNs compared to HLNs. Importantly, clinical outcome analysis revealed that DC clustering in tumor-positive TDLNs correlated with the duration of disease-free survival in breast cancer patients. Conclusions: These findings are the first to describe the spatial organization of DCs within TDLNs and their association with survival outcome. In addition, we characterized specific changes in number, size, maturity, and T cell co-localization of such clusters. Strategies to enhance DC function in-vivo, including maturation and clustering, may provide additional tools for developing more efficacious DC cancer vaccines.

引用

页数：12

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