2. Academic Validation
  3. MFGE8 induces anti-PD-1 therapy resistance by promoting extracellular vesicle sorting of PD-L1

MFGE8 induces anti-PD-1 therapy resistance by promoting extracellular vesicle sorting of PD-L1

  • Cell Rep Med. 2025 Jan 16:101922. doi: 10.1016/j.xcrm.2024.101922.
Wenhui Wang 1,  Jiming Chen 2,  Shibo Wang 1,  Xinhai Sun 3,  Jie Yang 4,  Pengfei Yu 5,  Guinv Hu 6,  Jiang Wang 6,  Jing Zhang 7,  Shuya Qiao 1,  Jianli Wang 8,  Gensheng Zhang 4,  Yuzhou He 9,  Huajun Feng 10,  Zhijian Cai 11
Affiliations

Affiliations

  • 1 Department of Orthopaedics of the Second Affiliated Hospital and Institute of Immunology, Zhejiang University School of Medicine, Hangzhou 310009, China.
  • 2 Key Laboratory of Functional and Clinical Translational Medicine, Fujian Province University, Xiamen Medical College, Xiamen 361023, China; Institute of Respiratory Diseases Xiamen Medical College, Xiamen 361023, China; Organiod Platform of Medical Laboratory Science, Xiamen Medical College, Xiamen 361023, China.
  • 3 Department of Thoracic Surgery, Fujian Institute of Thoracic and Cardiac Surgery, Fujian Medical University Union Hospital, Fuzhou 350001, China.
  • 4 Department of Critical Care Medicine of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China.
  • 5 Department of Abdominal Surgery, Zhejiang Cancer Hospital, Hangzhou 310022, China.
  • 6 Department of Thyroid and Breast Surgery, Affiliated Dongyang Hospital of Wenzhou Medical University, Dongyang 322100, China.
  • 7 Department of Pathology, Zhejiang University First Affiliated Hospital and School of Medicine, Hangzhou 310002, China.
  • 8 Institute of Immunology and Bone Marrow Transplantation Center of the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China; Institute of Hematology, Zhejiang University & Zhejiang Engineering Laboratory for Stem Cell and Immunotherapy, Hangzhou 310006, China.
  • 9 Ecological-Environment & Health College, Zhejiang A & F University, Hangzhou 311300, China; Department of Emergency, The Second Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou 310053, China. Electronic address: hyzxy1995@126.com.
  • 10 Ecological-Environment & Health College, Zhejiang A & F University, Hangzhou 311300, China. Electronic address: fenghuajun@zafu.edu.cn.
  • 11 Department of Orthopaedics of the Second Affiliated Hospital and Institute of Immunology, Zhejiang University School of Medicine, Hangzhou 310009, China. Electronic address: caizj@zju.edu.cn.
PMID: 39842432 DOI: 10.1016/j.xcrm.2024.101922
Abstract

Anti-PD-1 therapy, effective in patients with various advanced tumors, still encounters the challenge of insensitivity in most patients. Here, we demonstrate that PD-L1 on tumor cell-derived extracellular vesicles (TEVs) is critical for anti-PD-1 therapy resistance. Reducing endogenous and transferring exogenous TEVs abrogates and induces anti-PD-1 therapy resistance, respectively. Notably, PD-L1 is sorted onto TEVs via the endosomal sorting complex required for transport after ubiquitination by UBE4A and gradually upregulated on TEVs with tumor progression. During progression, increased MFGE8 from tumor cells promotes self αv Integrin signaling activation, enabling themselves to upregulate UBE4A, thereby increasing PD-L1 on TEVs and enhancing their immunosuppressive abilities. Translationally, anti-MFGE8-neutralizing Antibodies effectively downregulate UBE4A and TEV PD-L1, thereby negating anti-PD-1 therapy resistance. Furthermore, serum MFGE8 and PD-L1+ EV levels of tumor patients correlate positively, and high levels of both indicate poor prognosis after anti-PD-1 therapy. Thus, MFGE8 is a promising target for overcoming resistance and predicting responsiveness to anti-PD-1 therapy.

Keywords

MFGE8; PD-L1; UBE4A; anti-PD-1 therapy resistance; extracellular vesicles.

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