Alterations in the Immune Cell Composition in Premalignant Breast Tissue that Precede Breast Cancer Development

Degnim, Amy C.; Hoskin, Tanya L.; Arshad, Muhammad Usman; Frost, Marlene H.; Winham, Stacey J.; Brahmbhatt, Rushin D.; Peña, Alvaro; Carter, Jodi M.; Stallings-Mann, Melody; Murphy, Linda; Miller, Erin; Denison, Lori A.; Vachon, Celine M.; Knutson, Keith L.; Radisky, Derek C.; Visscher, Daniel W.

doi:10.1158/1078-0432.ccr-16-2026

Cited by 55 publications

(52 citation statements)

References 40 publications

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“…These data suggest that CLS-B-associated adipose tissue inflammation occurs in a significant subset of individuals with BBD. We have previously reported that lobules of BBD tissues have a significantly higher density of CD68-positive macrophages, among other immune cell types, compared with that of lobules in KTB donor breast tissues (24). Together, these findings support the hypothesis that BBD is associated with an epithelial and stromal chronic inflammatory environment.…”

Section: Discussionsupporting

confidence: 76%

Macrophagic “Crown-like Structures” Are Associated with an Increased Risk of Breast Cancer in Benign Breast Disease

Carter

Hoskin

Pena

et al. 2018

Cancer Prevention Research

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In breast adipose tissue, macrophages that encircle damaged adipocytes form "crown-like structures of breast" (CLS-B). Although CLS-B have been associated with breast cancer, their role in benign breast disease (BBD) and early carcinogenesis is not understood. We evaluated breast biopsies from three age-matched groups ( = 86 each, mean age 55 years), including normal tissue donors of the Susan G. Komen for the Cure Tissue Bank (KTB), and subjects in the Mayo Clinic Benign Breast Disease Cohort who developed cancer (BBD cases) or did not develop cancer (BBD controls, median follow-up 14 years). Biopsies were classified into histologic categories, and CD68-immunostained tissue sections were evaluated for the frequency and density of CLS-B. Our data demonstrate that CLS-B are associated with BBD: CLS-B-positive samples were significantly less frequent among KTB biopsies (3/86, 3.5%) than BBD controls (16/86 = 18.6%, = 0.01) and BBD cases (21/86 = 24%, = 0.002). CLS-B were strongly associated with body mass index (BMI); BMI < 25: 7% CLS-B positive, BMI 25-29: 13%, and BMI ≥ 30: 29% ( = 0.0005). Among BBD biopsies, a high CLS-B count [>5 CLS-B/sample: 10.5% (BBD cases) vs 4.7% (BBD controls), = 0.007] conferred a breast cancer OR of 6.8 (95% CI, 1.4-32.4), = 0.02, after adjusting for adipose tissue area (cm), histologic impression, and BMI. As high CLS-B densities are independently associated with an increased breast cancer risk, they may be a promising histologic marker of breast cancer risk in BBD. .

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Section: Discussionsupporting

confidence: 76%

Macrophagic “Crown-like Structures” Are Associated with an Increased Risk of Breast Cancer in Benign Breast Disease

Carter

Hoskin

Pena

et al. 2018

Cancer Prevention Research

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“…In benign breast disease tissues, we observe decreasing CD8+/CD103+ cells with increasing epithelial proliferation. This is particularly interesting given that our previous study showed higher densities of other immune cell types in lobules of BBD compared to normal tissues, suggesting greater inflammation in these tissues [8]. Activation of NFkb, a hallmark of inflammation, is a major factor in downregulation of E-cadherin in epithelial cells [16].…”

Section: Discussionmentioning

confidence: 86%

“…In most of these studies, the CD103expressing T cells were predominantly intraepithelial and CD103+ cells were more strongly associated with outcomes than CD8+ T cells. We recently reported on immune cells in normal and premalignant breast tissues, with a finding of CD8+ T cells in close association with breast epithelium, representing the main characteristic of mucosal IELs [8]. Therefore, we hypothesized that breast epithelium also harbors similar cytotoxic T cells that may play a role in antitumor immunity.…”

Section: Introductionmentioning

confidence: 91%

“…We obtained Institutional Review Board approval prior to conducting this research. We utilized samples from an existing study of breast tissues from normal donor women and women with benign breast disease [8]. Briefly, normal breast tissues were obtained from the Susan G. Komen ® for the Cure Tissue Bank at IU Simon Cancer Center (i.e.…”

Section: Study Design and Breast Tissue Samplesmentioning

confidence: 99%

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Cytotoxic T cell depletion with increasing epithelial abnormality in women with benign breast disease

Adhikary

Hoskin

Stallings-Mann

et al. 2020

Breast Cancer Res Treat

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Purpose We quantified cytotoxic T cells in nonmalignant breast tissues from women with and without subsequent breast cancer to assess evidence of whether immunosurveillance may be suppressed prior to tumor development. Methods We used an age-matched set of breast tissues from women with benign breast disease (BBD) who subsequently developed breast cancer (BBD with later BC), women with BBD who remained cancer free (BBD cancer-free), and normal Komen Tissue Bank (KTB) tissue donors (KTB controls). We evaluated terminal duct lobular units (lobules) for degree of epithelial abnormality and density of dual-positive CD8/CD103 T cells, as CD103+ cells are thought to be a subset of CD8+ cytotoxic T cells located primarily in the intraepithelial compartment. Results In 10 sets of age-matched women, 256 breast lobules were studied: 85 in BBD women with later BC, 85 in BBD cancer-free women, and 86 in KTB donors. The majority of all lobules were histologically normal (N = 143, 56%), with 65 (25%) nonproliferative fibrocystic change, and 48 (19%) proliferative epithelial change (with or without atypia). In BBD women with later BC, median CD8+/CD103+ cell density was 39.6, 31.7, and 10.5 cells/mm 2 (p = 0.002) for normal, nonproliferative, and proliferative lobules. In BBD cancer-free women, median CD8+/CD103+ cell density values were 46.7, 14.3, and 0 cells/mm 2 (p = 0.004) respectively. In KTB donors, CD8+/CD103+ cell density was not significantly different across the lobule types (medians 0, 5.8, 10.7, p = 0.43). Conclusion In women with BBD, breast lobules with increasing epithelial abnormality show significant decreases in cytotoxic T cells as measured by CD8/CD103 staining, suggesting that impaired immunosurveillance may be a component of the earliest stages of breast cancer development.

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“…The underlying mechanism may be that B cells promote T‐cell antitumor immune responses by acting as APCs. Likewise, the conclusion has been confirmed in melanoma, breast cancer and colorectal cancer . These results are also consistent with a previous study, which demonstrated that B cells were required for optimal induction of CD4 + and CD8 + T cells in controlling tumor invasion and metastasis .…”

Section: Dual Aspects Of the Biological Function Of B Cellsmentioning

confidence: 99%

A new perspective: Exploring future therapeutic strategies for cancer by understanding the dual role of B lymphocytes in tumor immunity

Liu

Sun

Wang

et al. 2018

Intl Journal of Cancer

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Our previous understanding of the role of B lymphocytes in tumor immunity is its antitumor effects. However, further evidence indicates B lymphocytes can also promote tumorigenesis by modulating immune responses. Therefore, the increasingly complex role of B lymphocytes in tumor immunity may become an important factor in tumor immunotherapy. In this review, we describe the development of B cells in tumor microenvironments. We then focus on the most controversial issues of the biological functions of B lymphocytes. Finally, we nominate B cells as therapeutic targets, which should open broad perspectives for the development of their clinical applications.

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Alterations in the Immune Cell Composition in Premalignant Breast Tissue that Precede Breast Cancer Development

Cited by 55 publications

References 40 publications

Macrophagic “Crown-like Structures” Are Associated with an Increased Risk of Breast Cancer in Benign Breast Disease

Macrophagic “Crown-like Structures” Are Associated with an Increased Risk of Breast Cancer in Benign Breast Disease

Cytotoxic T cell depletion with increasing epithelial abnormality in women with benign breast disease

A new perspective: Exploring future therapeutic strategies for cancer by understanding the dual role of B lymphocytes in tumor immunity

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