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Open Access Research

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

Andrew Y Chang1, Nupur Bhattacharya1, Jian Mu2, A Francesca Setiadi1, Valeria Carcamo-Cavazos1, Gerald H Lee1, Diana L Simons17, Sina Yadegarynia1, Kaveh Hemati1, Adam Kapelner3, Zheng Ming4, David N Krag5, Erich J Schwartz6, Danny Z Chen2 and Peter P Lee17*

  • * Corresponding author: Peter P Lee plee@coh.org

  • † Equal contributors

Author Affiliations

1 Department of Medicine, Stanford University, 269 Campus Drive, 94305 Stanford, CA, USA

2 Department of Computer Science and Engineering, University of Notre Dame, 384 Fitzpatrick Hall, 46556 Notre Dame, IN, USA

3 Department of Statistics, The Wharton School of the University of Pennsylvania, 400 Jon M. Huntsman Hall, 3730 Walnut Street, 19104 Philadelphia, PA, USA

4 Department of Anesthesia, School of Medicine, Stanford University, 300 Pasteur Drive, Room H3580, 94305 Stanford, CA, USA

5 University of Vermont College of Medicine, E309C Given Building, 89 Beaumont Avenue, 05405 Burlington, VT, USA

6 Department of Pathology, Stanford University, 300 Pasteur Drive, Lane 235, 94305 Stanford, CA, USA

7 Cancer Immunotherapeutics & Tumor Immunology, City of Hope and Beckman Research Institute, 1500 East Duarte Road, 91010 Duarte, CA, USA

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Journal of Translational Medicine 2013, 11:242  doi:10.1186/1479-5876-11-242

Published: 2 October 2013

Abstract

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.

Keywords:
Breast cancer; Immune cells; Dendritic cells; Clustering; Spatial organization; Lymph nodes