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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

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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 8

TSLP suppresses primary pancreatic tumor growth.

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TSLP suppresses primary pancreatic tumor growth.
(A) Graph shows the ave...
(A) Graph shows the average volume of P48+/Cre LSL-KRASG12D p53fl/+ pancreatic tumors transferred into WT and K14-TSLPtg mice over time. (B) Representative images show tumors 30 days after implantation of primary pancreatic tumor cells into the right flank of 6- to 8-week-old WT and K14-TSLPtg mice. Scale bar: 1 cm. (C) Bar graph shows the percentage of T-bet+ Th1 cells, GATA3+ Th2 cells, and FOXP3+ Tregs in the pancreatic tumors formed in WT and K14-TSLPtg animals. (D) Representative flow cytometric plots demonstrate FOXP3, GATA3, and T-bet expression in tumor-infiltrating CD4+ T cells in recipient mice. The data were reproduced in 2 independent experiments (n = 6 in each group; *P < 0.05 compared with WT, Student’s t test). Detailed experimental procedures are available in the Supplemental material.

Copyright © 2023 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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