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Published on: November 28, 2019
Extracellular vesicle-packaged PD-L1 impedes macrophage-mediated antibacterial immunity in preexisting malignancy
He-Jing Zhang1, Lingxin Zhu2, Qi-Hui Xie2
1State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan 430079, China; Department of Oral and Maxillofacial Surgery, School and Hospital of Stomatology, Wuhan University, Wuhan 430079, China.
Abstract:
Malignancies can compromise systemic innate immunity, but the underlying mechanisms are largely unknown. Here, we find that tumor-derived small extracellular vesicles (sEVs; TEVs) deliver PD-L1 to host macrophages, thereby impeding antibacterial immunity. Mice implanted with Rab27a-knockdown tumors are more resistant to bacterial infection than wild-type controls. Injection of TEVs into mice impairs macrophage-mediated bacterial clearance, increases systemic bacterial dissemination, and enhances sepsis score in a PD-L1-dependent manner. Mechanistically, TEV-packaged PD-L1 inhibits Bruton's tyrosine kinase/PLCγ2 signaling-mediated cytoskeleton reorganization and reactive oxygen species generation, impacting bacterial phagocytosis and killing by macrophages. Neutralizing PD-L1 markedly normalizes macrophage-mediated bacterial clearance in tumor-bearing mice. Importantly, circulating sEV PD-L1 levels in patients with tumors can predict bacterial infection susceptibility, while patients with tumors treated with αPD-1 exhibit fewer postoperative infections. These findings identify a mechanism by which cancer cells dampen host innate immunity-mediated bacterial clearance and suggest targeting TEV-packaged PD-L1 to reduce bacterial infection susceptibility in tumor-bearing conditions.
Insights
Tumor cells release vesicles carrying PD-L1, which weakens macrophage antibacterial immunity. Targeting this mechanism may reduce infection risk in cancer patients.
Area of Science:
- Immunology
- Oncology
- Cell Biology
Background:
- Malignancies impair systemic innate immunity through poorly understood mechanisms.
- Tumor-derived small extracellular vesicles (sEVs) are implicated in cancer progression and immune modulation.
Purpose of the Study:
- To investigate the role of tumor-derived sEVs (TEVs) in suppressing antibacterial immunity.
- To elucidate the mechanism by which TEVs impact macrophage function and bacterial clearance.
Main Methods:
- Utilized mouse models with wild-type and Rab27a-knockdown tumors to assess bacterial infection resistance.
- Administered TEVs to mice to evaluate effects on macrophage-mediated bacterial clearance and sepsis.
- Investigated the molecular signaling pathways (BTK/PLCγ2) affected by TEV-packaged PD-L1 in macrophages.
- Analyzed circulating sEV PD-L1 levels in cancer patients for correlation with infection susceptibility.
Main Results:
- Rab27a-knockdown tumors conferred increased resistance to bacterial infection.
- TEV injection impaired macrophage bacterial clearance, increased dissemination, and worsened sepsis in a PD-L1-dependent manner.
- TEV-packaged PD-L1 inhibited macrophage phagocytosis and bacterial killing via the BTK/PLCγ2 pathway.
- Elevated circulating sEV PD-L1 levels predicted infection susceptibility in cancer patients.
- Patients treated with αPD-1 experienced fewer postoperative infections.
Conclusions:
- Tumor-derived sEVs deliver PD-L1 to macrophages, suppressing innate antibacterial immunity.
- TEV-packaged PD-L1 disrupts macrophage phagocytosis and killing mechanisms.
- Circulating sEV PD-L1 is a potential biomarker for infection risk in cancer patients.
- Targeting TEV-packaged PD-L1 may mitigate bacterial infections in cancer patients.
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