Leukocyte composition of human breast cancer

Department of Pathology and Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA 94143, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 08/2011; 109(8):2796-801. DOI: 10.1073/pnas.1104303108
Source: PubMed


Retrospective clinical studies have used immune-based biomarkers, alone or in combination, to predict survival outcomes for women with breast cancer (BC); however, the limitations inherent to immunohistochemical analyses prevent comprehensive descriptions of leukocytic infiltrates, as well as evaluation of the functional state of leukocytes in BC stroma. To more fully evaluate this complexity, and to gain insight into immune responses after chemotherapy (CTX), we prospectively evaluated tumor and nonadjacent normal breast tissue from women with BC, who either had or had not received neoadjuvant CTX before surgery. Tissues were evaluated by polychromatic flow cytometry in combination with confocal immunofluorescence and immunohistochemical analysis of tissue sections. These studies revealed that activated T lymphocytes predominate in tumor tissue, whereas myeloid lineage cells are more prominant in "normal" breast tissue. Notably, residual tumors from an unselected group of BC patients treated with neoadjuvant CTX contained increased percentages of infiltrating myeloid cells, accompanied by an increased CD8/CD4 T-cell ratio and higher numbers of granzyme B-expressing cells, compared with tumors removed from patients treated primarily by surgery alone. These data provide an initial evaluation of differences in the immune microenvironment of BC compared with nonadjacent normal tissue and reveal the degree to which CTX may alter the complexity and presence of selective subsets of immune cells in tumors previously treated in the neoadjuvant setting.

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Available from: Alfred Au, Jan 14, 2015
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    • "Tumorinfiltrating leukocytes play dual roles in cancer, with the potential to either restrain or facilitate tumorigenesis. Most solid tumors are infiltrated by leukocytes with diverse profiles [4] , possibly reflecting the tissue of origin and tumor stage567 . However , the precise role of driver genes in mediating leukocyte infiltration and function has been largely unexplored. "

    Full-text · Dataset · Feb 2016
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    • "Insufficient attention was given to the intratumoral heterogeneity of TAM subtypes, in particular in relation to the different intratumoral structures. In human breast cancer following intratumoral compartments can be defined: (1) areas with soft fibrous stroma characterized by pronounced inflammatory infiltrates that are beneficial for invasive cell growth (Ham and Moon, 2013); (2) areas with coarse fibrous stroma containing collagen fibers and characterized by impaired synthesis of extracellular matrix proteins (ECM) (Campbell et al., 2011; Eiro et al., 2012; Ruffell et al., 2012; Tang, 2013); (3) areas of maximum stromaland-parenchymal relationship revealing certain similarities with soft fibrous stroma (Mahmoud et al., 2012); (4) parenchymal elements ; (5) gaps of ductal tumor structures (Pinder, 2010). All five stromal subtypes demonstrate functionally distinct areas of tumor mircoenvironment with not yet identified mechanistic role in metastatic spread. "
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    ABSTRACT: Tumor associated macrophages (TAM) support tumor growth and metastasis in several animal models of breast cancer, and TAM amount is predictive for efficient tumor growth and metastatic spread via blood circulation. However, limited information is available about intratumoral TAM heterogeneity and functional role of TAM subpopulations in tumor progression. The aim of our study was to examine correlation of TAM presence in various morphological segments of human breast cancer with clinical parameters. Thirty six female patients with nonspecific invasive breast cancer T1-4N0-3M0 were included in the study. Morphological examination was performed using Carl Zeiss Axio Lab.A1 and MiraxMidiZeiss. Immunohistochemical and immunofluorescence/confocal microcopy analysis was used to detect CD68 and stabilin-1 in 5 different tumor segments: (1) areas with soft fibrous stroma; (2) areas with coarse fibrous stroma; (3) areas of maximum stromal-and-parenchymal relationship; (4) parenchymal elements; (5) gaps of ductal tumor structures. The highest expression of CD68 was in areas with soft fibrous stroma or areas of maximum stromal-and-parenchymal relationship (79%). The lowest expression of CD68 was in areas with coarse fiber stroma (23%). Inverse correlation of tumor size and expression of CD68 in gaps of tubular tumor structures was found (R=-0.67; p=0.02). In case of the lymph node metastases the average score of CD68 expression in ductal gaps tumor structures was lower (1.4±0.5) compared to negative lymph nodes case (3.1±1.0; F=10.9; p=0.007). Confocal microscopy identified 3 phenotypes of TAM: CD68(+)/stabilin-1(-); CD68(+)/stabilin-1(+) (over 50%); and CD68(-)/stabilin-1(+). However, expression of stabilin-1 did not correlate with lymph node metastasis. We concluded, that increased amount of CD68+TAM in gaps of ductal tumor structures is protective against metastatic spread in regional lymph nodes.
    Full-text · Article · Sep 2015 · Immunobiology
    • "In many cancer types tumor associated macrophages (TAMs) are the most abundant immune cell population [14]. Clinically, elevated levels of TAMs are often associated with poor response to therapy as well as pathophysiological features such as (neo)vascularization , invasiveness, metastasis, and immunosuppression [15] [16] [17]. "
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    ABSTRACT: It is becoming increasingly accepted that macrophages play a crucial role in many diseases associated with chronic inflammation, including atherosclerosis, obesity, diabetes, cancer, skin diseases, and even neurodegenerative diseases. It is therefore not surprising that macrophages in human diseases have gained significant interest during the last years. Molecular analysis combined with more sophisticated murine disease models and the application of genome-wide technologies has resulted in a much better understanding of the role of macrophages in human disease. We highlight important gain of knowledge during the last years for tumor-associated macrophages, and for macrophages in atherosclerosis, obesity and wound healing. Albeit these exciting findings certainly pave the way to novel diagnostics and therapeutics, several hurdles still need to be overcome. We propose a general outline for future research and development in disease-related macrophage biology based on integrating (1) genome-wide technologies, (2) direct human sampling, and (3) a dedicated use of in vivo model systems. Copyright © 2015 Elsevier Ltd. All rights reserved.
    No preview · Article · Aug 2015 · Seminars in Immunology
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