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 4

TSLP induces the accumulation of CD4+ T cells and their polarization to Th2 cells in breast tumors and their draining lymph nodes.

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TSLP induces the accumulation of CD4+ T cells and their polarization to ...
(A) Cytokine profiling of the tumor-draining lymph nodes revealed that the Th2-polarized cytokine milieu dominated in K14-TSLPtg PyMttg animals. Bar graphs show the relative mRNA expression of several Th1- and Th2-related cytokines versus Gapdh in K14-TSLPtg PyMttg tumor–draining lymph nodes compared with PyMttg tumor–draining lymph nodes (n = 4 per group; *P < 0.05 compared with PyMttg, Student’s t test). (B) Th2 cells formed the dominant type of T cells infiltrating the K14-TSLPtg PyMttg breast tumors. Representative flow cytometric plots show the percentage of CD4+ and CD8+ T cells in PyMttg and K14-TSLPtg PyMttg breast tumors. T-bet, GATA3, and FOXP3 transcription factor staining delineated the characteristics of the tumor-infiltrating CD4+ T cells in PyMttg and K14-TSLPtg PyMttg animals. Flow cytometric data were reproduced in 6 independent experiments. Data were collected when PyMttg animals had reached the metastatic breast cancer endpoint. Numbers in the flow cytometric plots represent the percentage of the plotted cell population. Bar graph demonstrates the percentage of Th1 and Th2 cells and Tregs within the PyMttg and K14-TSLPtg PyMttg breast tumors (n ≥4 per group; *P < 0.05 compared with PyMttg, Student’s t test).