Fibroblast-Derived IL33 Facilitates Breast Cancer Metastasis by Modifying the Immune Microenvironment and Driving Type 2 Immunity

Lungs are one of the main sites of breast cancer metastasis. The metastatic microenvironment is essential to facilitate growth of disseminated tumor cells. Cancer-associated fibroblasts (CAF) are prominent players in the microenvironment of breast cancer. However, their role in the formation of a pe...

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Bibliographic Details
Published in:Cancer research (Chicago, Ill.) Ill.), 2020-12, Vol.80 (23), p.5317-5329
Main Authors: Shani, Ophir, Vorobyov, Tatiana, Monteran, Lea, Lavie, Dor, Cohen, Noam, Raz, Yael, Tsarfaty, Galia, Avivi, Camila, Barshack, Iris, Erez, Neta
Format: Article
Language:English
Subjects:
Animals
Breast Neoplasms - immunology
Breast Neoplasms - pathology
Cancer-Associated Fibroblasts - metabolism
Cancer-Associated Fibroblasts - pathology
Female
Fibroblasts - metabolism
Humans
Interleukin-1 Receptor-Like 1 Protein - metabolism
Interleukin-33 - antagonists & inhibitors
Interleukin-33 - immunology
Interleukin-33 - metabolism
Lung - cytology
Lung Neoplasms - immunology
Lung Neoplasms - pathology
Lung Neoplasms - secondary
Mice, Inbred BALB C
Mice, Transgenic
Stromal Cells - metabolism
Stromal Cells - pathology
T-Lymphocytes - immunology
T-Lymphocytes - metabolism
Tumor Microenvironment - immunology
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Summary:Lungs are one of the main sites of breast cancer metastasis. The metastatic microenvironment is essential to facilitate growth of disseminated tumor cells. Cancer-associated fibroblasts (CAF) are prominent players in the microenvironment of breast cancer. However, their role in the formation of a permissive metastatic niche is unresolved. Here we show that IL33 is upregulated in metastases-associated fibroblasts in mouse models of spontaneous breast cancer metastasis and in patients with breast cancer with lung metastasis. Upregulation of IL33 instigated type 2 inflammation in the metastatic microenvironment and mediated recruitment of eosinophils, neutrophils, and inflammatory monocytes to lung metastases. Importantly, targeting of IL33 resulted in inhibition of lung metastasis and significant attenuation of immune cell recruitment and type 2 immunity. These findings demonstrate a key function of IL33 in facilitating lung metastatic relapse by modulating the immune microenvironment. Our study shows a novel interaction axis between CAF and immune cells and reveals the central role of CAF in establishing a hospitable inflammatory niche in lung metastasis. SIGNIFICANCE: This study elucidates a novel role for fibroblast-derived IL33 in facilitating breast cancer lung metastasis by modifying the immune microenvironment at the metastatic niche toward type 2 inflammation.
ISSN:0008-5472
1538-7445
DOI:10.1158/0008-5472.CAN-20-2116