2. Academic Validation
  3. Tumour cell-released autophagosomes promote lung metastasis by upregulating PD-L1 expression in pulmonary vascular endothelial cells in breast cancer

Tumour cell-released autophagosomes promote lung metastasis by upregulating PD-L1 expression in pulmonary vascular endothelial cells in breast cancer

  • Cell Oncol (Dordr). 2024 Oct 7. doi: 10.1007/s13402-024-00994-y.
Xu-Ru Wang # 1,  Xiao-He Zhou # 1,  Xiao-Tong Sun # 2,  Yu-Qing Shen # 1,  Yu-Yang Wu 1,  Cheng-Dong Wu 1,  Feng-Jiao Zhu 1,  Yi-Ting Wei 3,  Jin-Peng Chen 4,  Jing Chen 1,  Shi-Ya Zheng 5,  Li-Xin Wang 6 7 8
Affiliations

Affiliations

  • 1 Department of Microbiology and Immunology, School of Medicine, Jiangsu Provincial Key Laboratory of Critical Care Medicine, Southeast University, Nanjing, 210009, China.
  • 2 Department of Laboratory Medicine, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, Shandong, 264000, China.
  • 3 Jiangsu Provincial Key Laboratory of Critical Care Medicine, Department of Critical Care Medicine, Zhongda Hospital, Medical School of Southeast University, Nanjing, 210009, China.
  • 4 Department of General Surgery, Zhongda Hospital, Medical School of Southeast University, Nanjing, 210009, China.
  • 5 Department of Oncology, Zhongda Hospital, Medical School of Southeast University, Nanjing, 210009, China.
  • 6 Department of Microbiology and Immunology, School of Medicine, Jiangsu Provincial Key Laboratory of Critical Care Medicine, Southeast University, Nanjing, 210009, China. lxwang@seu.edu.cn.
  • 7 Jiangsu Provincial Key Laboratory of Critical Care Medicine, Department of Critical Care Medicine, Zhongda Hospital, Medical School of Southeast University, Nanjing, 210009, China. lxwang@seu.edu.cn.
  • 8 Department of Microbiology and Immunology, Medical School of Southeast University, 87 Dingjiaqiao Road, Nanjing, Jiangsu Province, 210009, China. lxwang@seu.edu.cn.
  • # Contributed equally.
PMID: 39373859 DOI: 10.1007/s13402-024-00994-y
Abstract

Purpose: Establishing an immunosuppressive premetastatic niche (PMN) in distant organs is crucial for breast Cancer metastasis. Vascular endothelial cells (VECs) act as barriers to transendothelial cell migration. However, the immune functions of PMNs remain unclear. Tumour cell-released autophagosomes (TRAPs) are critical modulators of antitumour immune responses. Herein, we investigated the mechanism through which TRAPs modulate the immune function of pulmonary VECs in lung PMN in breast Cancer.

Methods: Immortalised mouse pulmonary microvascular endothelial cells were incubated with TRAPs in vitro. RNA Sequencing, flow cytometry, and western blotting were employed to assess immunosuppressive function and mechanism. In vivo, TRAP-trained and autophagy-deficient tumour mice were used to detect immunosuppression, and high-mobility group box 1 (HMGB1)-deficient TRAP-trained and TLR4 knockout mice were utilised to investigate the underlying mechanisms of pulmonary VECs. Additionally, the efficacy of anti-programmed cell death ligand-1 (PD-L1) immunotherapy was evaluated in early tumour-bearing mice.

Results: HMGB1 on TRAPs surfaces stimulated VECs to upregulate PD-L1 via a TLR4-MyD88-p38/STAT3 signalling cascade that depended on the cytoskeletal movement of VECs. Importantly, PD-L1 on TRAP-induced VECs can inhibit T cell function, promote lung PMN immunosuppression, and result in more pronounced lung metastasis. Treatment with anti-PD-L1 reduces lung metastasis in early stage tumour-bearing mice.

Conclusions: These findings revealed a novel role and mechanism of TRAP-induced immunosuppression of pulmonary VECs in lung PMN. TRAPs and their surface HMGB1 are important therapeutic targets for reversing immunosuppression, providing a new theoretical basis for the treatment of early stage breast Cancer using an anti-PD-L1 antibody.

Keywords

High mobility group box 1 (HMGB1); PD-L1; Premetastatic niche (PMN); Tumour cell-released autophagosomes (TRAPs); Vascular endothelial cells (VECs).

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