Thymic stromal lymphopoietin blocks early stages of breast carcinogenesis
Shadmehr Demehri, … , David G. DeNardo, Wayne M. Yokoyama
Shadmehr Demehri, … , David G. DeNardo, Wayne M. Yokoyama
Published February 29, 2016
Citation Information: J Clin Invest. 2016;126(4):1458-1470. https://doi.org/10.1172/JCI83724.
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Research Article Oncology

Thymic stromal lymphopoietin blocks early stages of breast carcinogenesis

Abstract

Advances in the field of cancer immunology, including studies on tumor-infiltrating CD8+ cytotoxic T lymphocytes (CTLs), have led to new immunotherapeutics with proven efficacy against late-stage cancers. However, the antitumor potential of the immune system in targeting early-stage cancers remains uncertain. Here, we demonstrated that both genetic and chemical induction of thymic stromal lymphopoietin (TSLP) at a distant site leads to robust antitumor immunity against spontaneous breast carcinogenesis in mice. Breast tumors exposed to high circulating levels of TSLP were arrested at an early adenoma-like stage and were prevented from advancing to late carcinoma and metastasis. Additionally, CD4+ Th2 cells mediated the antitumor effects of TSLP, challenging the notion that Th2 cells only promote cancer. We also discovered that TSLP is expressed by the breast tumor cells themselves and acts to block breast cancer promotion. Moreover, TSLP-induced immunity also blocked early stages of pancreatic cancer development. Together, our findings demonstrate that TSLP potently induces immunity directed against early stages of breast cancer development without causing inflammation in the normal breast tissue. Moreover, our results highlight a previously unappreciated function of the immune system in controlling the early development of cancer and establish a fundamental role for TSLP and Th2 cells in tumor immunity against early-stage cancers.

Authors

Shadmehr Demehri, Trevor J. Cunningham, Sindhu Manivasagam, Kenneth H. Ngo, Sara Moradi Tuchayi, Rasika Reddy, Melissa A. Meyers, David G. DeNardo, Wayne M. Yokoyama

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Figure 1

TSLP overexpression in the skin leads to allergic inflammation in barrier organs and induces a CD4+ T cell–mediated immune response to the developing breast tumors.

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TSLP overexpression in the skin leads to allergic inflammation in barrie...
(A) TSLP expression in the skin causes atopic dermatitis–like inflammation. Representative images of H&E and toluidine blue staining (highlighting mast cells in purple) of skin from 10-week-old WT, K14-TSLPtg, PyMttg, and K14-TSLPtg PyMttg mice are shown. The average number of mast cells in 10 random high-power fields (hpf) is shown as a bar graph at the left edge of the images (*P < 0.05 compared with WT, Student’s t test). (B) Elevated systemic TSLP levels caused inflammation in the lungs. Representative images of H&E and CD3 staining (marking T cells) of lungs from 10-week-old WT, K14-TSLPtg, PyMttg, and K14-TSLPtg PyMttg mice. Arrows point to the foci of inflammation around lung airways. Higher-magnification representative images of CD3-stained lung airways are shown. Bar graphs at the left edge of the CD3-stained images show the average number of lymphocyte aggregate foci per lung section in 10 random lungs from each cohort (*P < 0.05 compared with WT, Student’s t test). (C) TSLP induction led to accumulation of CD4+ T cells at the site of breast cancer development and to its arrest. Representative images of H&E, CD3 immunohistochemical, CD4, CD3, and cytokeratin (CK) immunofluorescence staining of breast glands and early tumors from 10-week-old WT, K14-TSLPtg, PyMttg, and K14-TSLPtg PyMttg mice. The average number of tumor-infiltrating CD4+ T cells in 10 random hpf is shown as a bar graph at the left edge of the immunofluorescence images (*P < 0.05 compared with WT, Student’s t test). Data were reproduced in 3 independent experiments. Scale bars: 100 μm.