Immune cell quantitation in normal breast tissue lobules with and without lobulitis

Degnim, Amy C.; Brahmbhatt, Rushin D.; Radisky, Derek C.; Hoskin, Tanya L.; Stallings-Mann, Melody; Laudenschlager, Mark; Mansfield, Aaron S.; Frost, Marlene H.; Murphy, Linda; Knutson, Keith L.; Visscher, Daniel W.

doi:10.1007/s10549-014-2896-8

Cited by 80 publications

(85 citation statements)

References 50 publications

(63 reference statements)

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“…The results presented here contrast with earlier studies of breast tissue, and demonstrate that the human breast epithelial organoid represents a specialized immunological niche that is comprised mainly of T cells (>90% of the CD45 + cells). In contrast to the composition of T cells from blood, the breast epithelial T cell population was markedly skewed towards CD8 + cells, which is consistent with a recent study demonstrating that CD8 T cells are directly integrated within the breast epithelium (7). Moreover, our observation that both the CD4 + and CD8 + T cells from the breast organoids had a CD27 − effector memory phenotype contrasts sharply with the dominant phenotypes of T cells from blood.…”

Section: Resultssupporting

confidence: 88%

“…Since breast cancers typically originate from the epithelial cells lining the mammary ducts and lobules (4), the immune cells responsible for immunosurveillance of transformed breast cells are likely to be those that patrol the ductal epithelium. Although recent studies have illustrated the presence of leukocytes in the human breast (5–8) and even in the epithelium (6, 7), the specific leukocyte subsets within this specialized tissue niche have remained poorly characterized. Moreover, a key unanswered question is whether immune cells are present that can be targeted to promote enhanced immunosurveillance of pre-cancerous or cancerous cells.…”

Section: Introductionmentioning

confidence: 99%

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Analysis of Immune Cells from Human Mammary Ductal Epithelial Organoids Reveals Vδ2+ T Cells That Efficiently Target Breast Carcinoma Cells in the Presence of Bisphosphonate

Zumwalde

Haag

Sharma

et al. 2016

Cancer Prevention Research

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Developing strategies to enhance cancer prevention is a paramount goal, particularly given recent concerns about surgical treatment of pre-invasive states such as ductal carcinoma in situ. Promoting effective immunosurveillance by leukocytes that scan for nascent neoplastic transformations represents a potential means to achieve this goal. Since most breast cancers arise within the ductal epithelium, enhancing protective immunosurveillance will likely necessitate targeting one or more of the distinctive lymphocyte types found in these sites under normal conditions. Here, we have characterized the intraepithelial lymphocyte compartment of non-cancerous human breast tissue and identified a subset of T lymphocytes that can be pharmacologically targeted to enhance their responses to breast cancer cells. Specifically, Vδ2+ γδ T cells were consistently present in preparations of mammary ductal epithelial organoids and they proliferated in response to zoledronic acid, an aminobisphosphonate drug. Vδ2+ T cells from breast ductal organoids produced the anti-tumor cytokine IFN-γ and efficiently killed bisphosphonate-pulsed breast carcinoma cells. These findings demonstrate the potential for exploiting the ability of Vδ2+ γδ T cells to respond to FDA-approved bisphosphonate drugs as a novel immunotherapeutic approach to inhibit the outgrowth of breast cancers.

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Section: Resultssupporting

confidence: 88%

Section: Introductionmentioning

confidence: 99%

Analysis of Immune Cells from Human Mammary Ductal Epithelial Organoids Reveals Vδ2+ T Cells That Efficiently Target Breast Carcinoma Cells in the Presence of Bisphosphonate

Zumwalde

Haag

Sharma

et al. 2016

Cancer Prevention Research

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“…Immune cells are closely associated with mammary epithelial cells (47) and contribute to a number of stages of mammary gland development. Macrophages affect development and regression of the mammary gland over the course of the cycle, and these alternating roles of macrophages may affect menstrual cycle-associated breast cancer risk, particularly during the process of mammary gland regression.…”

Section: Changes In the Immune Microenvironment During The Menstrual mentioning

confidence: 99%

Dissecting the Biology of Menstrual Cycle-Associated Breast Cancer Risk

et al. 2016

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Fluctuations in circulating estrogen and progesterone across the menstrual cycle lead to increased breast cancer susceptibility in women; however, the biological basis for this increased risk is not well understood. Estrogen and progesterone have important roles in normal mammary gland development, where they direct dynamic interactions among the hormonally regulated mammary epithelial, stromal, and immune cell compartments. The continuous fluctuations of estrogen and progesterone over a woman’s reproductive lifetime affect the turnover of mammary epithelium, stem cells, and the extracellular matrix, as well as regulate the phenotype and function of mammary stromal and immune cells, including macrophages and regulatory T cells. Collectively, these events may result in genome instability, increase the chance of random genetic mutations, dampen immune surveillance, and promote tolerance in the mammary gland, and thereby increase the risk of breast cancer initiation. This article reviews the current status of our understanding of the molecular and the cellular changes that occur in the mammary gland across the menstrual cycle and how continuous menstrual cycling may increase breast cancer susceptibility in women.

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“…Quantifying T-cells via sequencing is highly reproducible and correlates well with H&E staining but with higher sensitivity (29). Immunohistochemistry indicates that Tcells in healthy breast tissue are mostly located in lobules with CD8+ T-cells approximately 10-fold more abundant than CD4+ (38). Immune infiltrates isolated from tumor and normal breast contain similar amounts of CD8+ T-cells (~20% of T-cells) whereas CD4+ T-cells in tumor comprise ~40% of T-cells compared to ~20% in normal breast tissue (39).…”

Section: Discussionmentioning

confidence: 93%

T-cell receptor sequencing of early stage breast cancer tumors identifies altered clonal structure of the T-cell repertoire

Beausang¹,

Wheeler²,

Chan³

et al. 2017

Preprint

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Tumor infiltrating T-cells play an important role in many cancers, and can improve prognosis and yield therapeutic targets. We characterized T-cells infiltrating both breast cancer tumors and the surrounding normal breast tissue to identify T-cells specific to each, as well as their abundance in peripheral blood. Using immune profiling of the T-cell beta chain repertoire in 16 patients with early stage breast cancer, we show that the clonal structure of the tumor is significantly different from adjacent breast tissue, with the tumor containing approximately 3-fold more T-cells, but with a lower fraction of unique sequences and higher clonality compared to normal breast. The clonal structure of T-cells in blood and normal breast is more similar than between blood and tumor and can be used to distinguish tumor from normal breast tissue in 14 of 16 patients. Many T-cells overlap between tissues from the same patient, including approximately 50% of T-cells between tumor and normal breast. Both solid tissues contain high-abundance "enriched" sequences that are absent or of low abundance in the other tissue. Many of these T-cells are either not detected or detected with very low frequency in the blood, suggesting the existence of separate compartments of T-cells in both tumor and normal breast. Enriched T-cell sequences are typically unique to each patient, but there is a subset of sequences that are shared between many different patients. We show that most of these are commonly generated sequences and thus unlikely to play an important role in the tumor microenvironment. Significance StatementThe recent advances in cancer immunotherapy motivated us to investigate the clonal structure of the T cell receptor repertoire in breast tumors, normal breast and blood in the same individuals. We found quantitatively distinct clonal structures in all three tissues, which enabled us to predict whether tissue is normal or tumor solely by comparing the repertoire of the tissue to blood. T cell receptor sequences shared between patients tumors are rare and in general do not appear to be specific to the cancer.

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Immune cell quantitation in normal breast tissue lobules with and without lobulitis

Cited by 80 publications

References 50 publications

Analysis of Immune Cells from Human Mammary Ductal Epithelial Organoids Reveals Vδ2+ T Cells That Efficiently Target Breast Carcinoma Cells in the Presence of Bisphosphonate

Analysis of Immune Cells from Human Mammary Ductal Epithelial Organoids Reveals Vδ2+ T Cells That Efficiently Target Breast Carcinoma Cells in the Presence of Bisphosphonate

Dissecting the Biology of Menstrual Cycle-Associated Breast Cancer Risk

T-cell receptor sequencing of early stage breast cancer tumors identifies altered clonal structure of the T-cell repertoire

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