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

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. 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.

Interleukins in cancer: from biology to therapy

“…Tumour and stromal cells may secrete factors to pro mote T H 2 cell and M2 macrophage polarization, which suppress antitumoural T H 1 cell polarization and responses 135,136 . In the same way, IL33induced group 2 innate lymphoid cells (ILC2) were demonstrated to antago nize NK cell function in a mouse model of melanoma 137 .…”

“…In the same way, IL33induced group 2 innate lymphoid cells (ILC2) were demonstrated to antago nize NK cell function in a mouse model of melanoma 137 . In turn, IL33, secreted by cancerassociated fibro blasts in breast cancer, is a potent enhancer of ILC2 and T H 2-type responses, and may induce TCRindependent secretion of IL13 and recruitment of immunosup pressive granulocytes 58,135 . Moreover, IL33 activates intrinsic signalling in T reg cells necessary for their immunosuppressive action in cancer 124 .…”

Transition to invasive breast cancer is associated with progressive changes in the structure and composition of tumor stroma

“…With this in mind, we sought to determine to what extent similar features involving myoepithelial, stromal, and immune cells in the DCIS TME might play a pivotal role in breast cancer progression. Each of these have been implicated previously to promote local invasion (Barsky and Karlin, 2005;Ibrahim et al, 2020), metastasis (Pelon et al, 2020;Shani et al, 2020), and to correlate with clinical progression (Yang et al, 2018;Zhou et al, 2018).…”

Evolution of fibroblasts in the lung metastatic microenvironment is driven by stage-specific transcriptional plasticity

“…CAFs are known to play a central role in mediating tumor-promoting inflammation at the primary tumor site ( Servais and Erez, 2013 ). Importantly, activation of inflammation was also implicated in shaping of the metastatic microenvironment ( Coffelt et al, 2015 ; Quail et al, 2017 ; Albrengues et al, 2018 ), but the role of fibroblasts in mediating inflammation at the metastatic site is only recently emerging: recent studies implicated CAF-derived cytokines including IL-1β, IL-33, and CXCL9/10 in promoting breast cancer lung metastasis ( Pein et al, 2020 ; Ershaid et al, 2019 ; Shani et al, 2020 ). However, a comprehensive profiling of metastases-associated fibroblasts isolated from spontaneous metastasis in immune competent mice was not previously done.…”