Abstract
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 in vivo 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.
| Original language | English |
|---|---|
| Pages (from-to) | 5317-5329 |
| Number of pages | 13 |
| Journal | Cancer Research |
| Volume | 80 |
| Issue number | 23 |
| DOIs | |
| State | Published - 1 Dec 2020 |
| Externally published | Yes |
Bibliographical note
Publisher Copyright:© 2020 American Association for Cancer Research.
Funding
This research was supported by grants to N. Erez from the European Research Council (ERC) under the European Union’s Horizon 2020 Research and Innovation Programme (grant agreement No. 637069 MetCAF), from the Israel Science Foundation (#1060/18), the Emerson Collective, and the Israel Cancer Research Fund (ICRF Project Grant). The authors would like to thank Sharon Grisaru for her assistance with staining of eosinophils and Ariel Munitz for critical reading and useful discussion of the manuscript. This research was supported by grants to N. Erez from the European Research Council (ERC) under the European Union's Horizon 2020 Research and Innovation Programme (grant agreement No. 637069 MetCAF), from the Israel Science Foundation (#1060/18), the Emerson Collective, and the Israel Cancer Research Fund (ICRF Project Grant). The authors would like to thank Sharon Grisaru for her assistance with staining of eosinophils and Ariel Munitz for critical reading and useful discussion of the manuscript.
| Funders | Funder number |
|---|---|
| Emerson Collective | |
| Israel Cancer Research Fund | |
| Horizon 2020 Framework Programme | |
| European Commission | |
| Israel Science Foundation | 1060/18 |
| Horizon 2020 | 637069 |
