Tumor-derived exosomes drive pre-metastatic niche formation in lung via modulating CCL1+ fibroblast and CCR8+ Treg cell interactions.

Abstract

BACKGROUND:

Since the lung is one of the most common sites for cancer metastasis, it could provide a suitable microenvironment for pre-metastatic niche (PMN) formation to facilitate tumor cell colonization. Regulatory T cells (Tregs) are an immunosuppressive cell type found ubiquitously in tumors and may play a crucial role in PNM formation. In this study, we investigated tumor-derived exosome (TDE)-induced Treg differentiation in the lung PMN as well as the underlying mechanisms.

METHODS:

TDEs were isolated from the Lewis lung carcinoma cell line (LLC-exo) and their effects on mouse pulmonary fibroblasts was investigated in vitro as well as on lung tumor formation and metastasis in a pre-injected mouse model. Immune cell populations in the lung were analyzed by flow cytometry. Expression of CCL1 and CCR8 was evaluated by immunofluorescence staining, qRT-PCR and Western blot analyses. Cytokine expression was measured using mouse cytokine arrays and ELISA.

RESULTS:

The number of CD4+ FoxP3+ Tregs was significantly increased in lungs in a LLC-exo pre-injected mouse model. Lung fibroblasts secreted increased amounts of CCL1 after co-culture with LLC-exo, which induced Treg differentiation by activating its specific receptor CCR8, ultimately contributing to the establishment of an immunologically tolerant PMN. Moreover, inhibiting the release of LLC-exo by GW4869, or blocking the CCL1-CCR8 axis using AZ084, suppressed Tregs differentiation and tumor metastasis in the lung.

CONCLUSIONS:

Collectively, our study provides a novel mechanism by which Tregs are activated to form an immunologically tolerant PMN and demonstrates a critical link among lung fibroblasts, Tregs and metastatic tumor cells.

• Authors: Ming Wang, Zhongyu Qin, Jiajia Wan, Yan Yan, Xixi Duan, Xiaohan Yao, Ziming Jiang, Wenqing Li, Zhihai Qin
• Journal: Cancer immunology, immunotherapy : CII (Cancer Immunol Immunother) Vol. 71 Issue 11 Pg. 2717-2730 (Nov 2022) ISSN: 1432-0851 [Electronic] Germany
• PMID: 35428909 (Publication Type: Journal Article)
• Copyright: © 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.

Chemical References

• Ccr8 protein, mouse
• Chemokine CCL1
• Cytokines
• Forkhead Transcription Factors
• Receptors, CCR8

Topics

• Animals
• Mice
• Cell Communication
• Chemokine CCL1 (metabolism)
• Cytokines (metabolism)
• Exosomes (metabolism)
• Fibroblasts (metabolism)
• Forkhead Transcription Factors (metabolism)
• Lung (metabolism)
• Neoplasms (metabolism)
• Receptors, CCR8
• T-Lymphocytes, Regulatory
• Tumor Microenvironment