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 3

TSLP-induced breast cancer suppression is associated with accumulation of CD4+ T cells around the arrested breast tumor foci.

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TSLP-induced breast cancer suppression is associated with accumulation o...
(A) Breast gland development in K14-TSLPtg PyMttg female mice was intact, but the breast cancer promotion phase was inhibited in these animals. Representative images of carmine-stained (mammary ducts in red) breast glands and tumors from age-matched WT, K14-TSLPtg, PyMttg, and K14-TSLPtg PyMttg female mice when PyMttg animals had developed palpable tumors. (B) Endpoint histological analysis revealed CD4+ T cell infiltrate surrounding dilated mammary ducts in K14-TSLPtg PyMttg female mice. Representative images show H&E, CD4/CD3/CK, and CD8/CD3/CK immunofluorecence staining of adjacent sections of breast glands and tumors. Note that the tissues were from age-matched WT, K14-TSLPtg, PyMttg, and K14-TSLPtg PyMttg female mice when the PyMttg animals had developed terminal metastatic breast cancers. (C) The majority of T cells in K14-TSLPtg PyMttg tumors were CD4+ T cells. Bar graphs show the average number of tumor-infiltrating CD4+ and CD8+ T cells in 10 random hpf within the glands and tumors of WT, K14-TSLPtg, PyMttg, and K14-TSLPtg PyMttg mice (*P < 0.05 compared with PyMttg, Student’s t test). (D) At the terminal stage of cancer in PyMttg mice, circulating TSLP levels rose in PyMttg mice, but remained significantly higher in K14-TSLPtg and K14-TSLPtg PyMttg animals. Bar graph shows the serum TSLP levels in WT, K14-TSLPtg, PyMttg, and K14-TSLPtg PyMttg female mice when the PyMttg animals had reached the metastatic breast cancer endpoint (n = 4 per group; *P < 0.05 compared with WT, Student’s t test). Data were reproduced in 3 independent experiments. Scale bars: 100 μm.