MFGE8 induces anti-PD-1 therapy resistance by promoting extracellular vesicle sorting of PD-L1
Wenhui Wang1, Jiming Chen2, Shibo Wang1
1Department of Orthopaedics of the Second Affiliated Hospital and Institute of Immunology, Zhejiang University School of Medicine, Hangzhou 310009, China.
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.
Insights
Tumor cell-derived extracellular vesicles (TEVs) carrying PD-L1 drive resistance to anti-PD-1 therapy. Targeting MFGE8 can overcome this resistance and predict patient response.
Area of Science:
- Immunology
- Oncology
- Cell Biology
Background:
- Anti-PD-1 therapy is a crucial cancer treatment, but many patients exhibit resistance.
- The mechanisms underlying this resistance, particularly the role of tumor-derived factors, require further elucidation.
Purpose of the Study:
- To investigate the role of PD-L1 on tumor cell-derived extracellular vesicles (TEVs) in anti-PD-1 therapy resistance.
- To identify molecular mechanisms regulating PD-L1 sorting onto TEVs and its impact on tumor progression.
- To explore potential therapeutic strategies targeting this resistance mechanism.
Main Methods:
- Investigated the effect of manipulating TEVs on anti-PD-1 therapy response in preclinical models.
- Utilized ubiquitination and endosomal sorting complex assays to study PD-L1 trafficking.
- Examined the role of MFGE8 and αv integrin signaling in regulating UBE4A and TEV PD-L1.
- Assessed serum MFGE8 and PD-L1+ EV levels in cancer patients undergoing anti-PD-1 therapy.
Main Results:
- PD-L1 on TEVs was identified as a critical factor mediating resistance to anti-PD-1 therapy.
- PD-L1 is sorted onto TEVs via ubiquitination by UBE4A, with levels increasing during tumor progression.
- MFGE8 promotes UBE4A upregulation, enhancing PD-L1 loading onto TEVs and immunosuppression.
- Anti-MFGE8 antibodies reversed therapy resistance by downregulating UBE4A and TEV PD-L1.
- Elevated serum MFGE8 and PD-L1+ EVs correlated with poor prognosis in patients.
Conclusions:
- PD-L1 on TEVs is a key driver of anti-PD-1 therapy resistance.
- MFGE8 is a critical regulator of PD-L1 sorting onto TEVs and represents a promising therapeutic target.
- Serum MFGE8 and PD-L1+ EVs can serve as predictive biomarkers for anti-PD-1 therapy responsiveness.
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