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

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

  • Cancer Immunol Immunother. 2022 Nov;71(11):2717-2730. doi: 10.1007/s00262-022-03196-3.
Ming Wang  # 1 Zhongyu Qin  # 2 Jiajia Wan 3 Yan Yan 3 Xixi Duan 3 Xiaohan Yao 3 Ziming Jiang 4 Wenqing Li 3 Zhihai Qin 5 6
Affiliations

Affiliations

  • 1 Medical Research Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, 450052, Henan, China. wangmingheda@163.com.
  • 2 Changzhi Medical College, Changzhi, 046000, Shanxi, China.
  • 3 Medical Research Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, 450052, Henan, China.
  • 4 Department of Urology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China.
  • 5 Medical Research Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, 450052, Henan, China. zhihai@ibp.ac.cn.
  • 6 Academy of Medical Sciences, Zhengzhou University, Zhengzhou, 450052, Henan, China. zhihai@ibp.ac.cn.
  • # Contributed equally.
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.

Keywords

CCL1–CCR8; Fibroblasts; Metastasis; PMN; Tregs.

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