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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.

SUBMITTER: Shani O

PROVIDER: S-EPMC7611300 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundImmune checkpoint blockade (ICB) therapy holds promise in metastatic urothelial carcinoma (UC). Fibroblast growth factor receptor 3 (FGFR3) mutation drives T-cell-depleted microenvironment in UC, which led to the hypothesis that FGFR3 mutation might attenuate response to ICB in patients with metastatic UC. The study aims to compare prognosis and response between patients with FGFR3-mutated and FGFR3-wildtype metastatic UC after ICB therapy, and decode the potential molecular mechanisms.MethodsBased on the single-arm, multicenter, phase 2 trial, IMvigor210, we conducted a propensity score matched (PSM) analysis. After a 1:1 ratio PSM method, 39 patients with FGFR3-mutated and 39 FGFR3-wildtype metastatic UC treated with atezolizumab were enrolled. A meta-analysis through systematical database retrieval was conducted for validation. In addition, we performed single-cell RNA sequencing on three FGFR3-mutated and three FGFR3-wildtype UC tumors and analyzed 58,069 single cells.ResultsThe PSM analysis indicated FGFR3-mutated patients had worse overall survival (OS) in comparison to FGFR3-wildtype patients (HR=2.11, 95% CI=(1.16 to 3.85), p=0.015) receiving atezolizumab. The median OS was 9.2 months (FGFR3-mutated) versus 21.0 months (FGFR3-wildtype). FGFR3-mutated patients had lower disease control rate than FGFR3-wildtype patients (41.0% vs 66.7%, p=0.023). The meta-analysis involving 938 patients with metastatic UC confirmed FGFR3 mutation was associated with worse OS after ICB (HR=1.28, 95% CI=(1.04 to 1.59), p=0.02). Single-cell RNA transcriptome analysis identified FGFR3-mutated UC carried a stronger immunosuppressive microenvironment compared with FGFR3-wildtype UC. FGFR3-mutated UC exhibited less immune infiltration, and lower T-cell cytotoxicity. Higher TREM2+ macrophage abundance in FGFR3-mutated UC can undermine and suppress the T cells, potentially contributing to the formation of an immunosuppressive microenvironment. Lower inflammatory-cancer-associated fibroblasts in FGFR3-mutated UC recruited less chemokines in antitumor immunity but expressed growth factors to promote FGFR3-mutated malignant cell development. FGFR3-mutated UC carried abundance of malignant cells characterized by high hypoxia/metabolism and low interferon response phenotype.ConclusionsFGFR3 mutation can attenuate prognosis and response to ICB in patients with metastatic UC. FGFR3-mutated UC carries a stronger immunosuppressive microenvironment in comparison with FGFR3-wildtype UC. Inhibition of FGFR3 might activate the immune microenvironment, and the combination of FGFR inhibitor targeted therapy and ICB might be a promising therapeutic regimen in metastatic UC, providing important implications for UC clinical management.

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

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