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Studying the Effects of Tumor-Secreted Paracrine Ligands on Macrophage Activation using Co-Culture with Permeable Membrane Supports
Published on: November 28, 2019
CD73 in small extracellular vesicles derived from HNSCC defines tumour-associated immunosuppression mediated by
Tingwei Lu1, Zhen Zhang1, Jianjun Zhang1
1Department of Oral and Maxillofacial-Head & Neck Oncology, Shanghai Ninth People's Hospital, College of Stomatology, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Abstract:
Research on tumour cell-derived small extracellular vesicles (sEVs) that regulate tumour microenvironment (TME) has provided strategies for targeted therapy of head and neck squamous cell carcinoma (HNSCC). Herein, we demonstrated that sEVs derived from HNSCC cancer cells carried CD73 (sEVsCD73 ), which promoted malignant progression and mediated immune evasion. The sEVsCD73 phagocytosed by tumour-associated macrophages (TAMs) in the TME induced immunosuppression. Higher CD73high TAMs infiltration levels in the HNSCC microenvironment were correlated with poorer prognosis, while sEVsCD73 activated the NF-κB pathway in TAMs, thereby inhibiting immune function by increasing cytokines secretion such as IL-6, IL-10, TNF-α, and TGF-β1. The absence of sEVsCD73 enhanced the sensitivity of anti-PD-1 therapy through reversed immunosuppression. Moreover, circulating sEVsCD73 increased the risk of lymph node metastasis and worse prognosis. Taken together, our study suggests that sEVsCD73 derived from tumour cells contributes to immunosuppression and is a potential predictor of anti-PD-1 responses for immune checkpoint therapy in HNSCC.
Insights
Tumour cell-derived small extracellular vesicles carrying CD73 (sEVsCD73) promote head and neck cancer progression and immune evasion. Targeting sEVsCD73 may enhance anti-PD-1 therapy effectiveness in HNSCC patients.
Area of Science:
- Oncology
- Immunology
- Extracellular Vesicles Biology
Background:
- Small extracellular vesicles (sEVs) from tumour cells play a role in regulating the tumour microenvironment (TME).
- Targeted therapies for head and neck squamous cell carcinoma (HNSCC) are being developed based on sEVs' role in the TME.
Purpose of the Study:
- To investigate the role of CD73-carrying sEVs (sEVsCD73) derived from HNSCC cells in tumour progression and immune evasion.
- To evaluate the potential of sEVsCD73 as a biomarker for prognosis and response to anti-PD-1 therapy in HNSCC.
Main Methods:
- Characterization of sEVsCD73 derived from HNSCC cells.
- Analysis of sEVsCD73 phagocytosis by tumour-associated macrophages (TAMs) and their impact on immunosuppression.
- Assessment of CD73high TAMs infiltration and correlation with prognosis.
- Investigation of the NF-κB pathway activation in TAMs by sEVsCD73.
- Evaluation of the effect of sEVsCD73 absence on anti-PD-1 therapy sensitivity.
- Analysis of circulating sEVsCD73 levels and their association with metastasis and prognosis.
Main Results:
- sEVsCD73 derived from HNSCC cells promote malignant progression and immune evasion.
- Phagocytosis of sEVsCD73 by TAMs induces immunosuppression via NF-κB pathway activation, increasing immunosuppressive cytokines (IL-6, IL-10, TNF-α, TGF-β1).
- Higher CD73high TAMs infiltration correlates with poorer HNSCC prognosis.
- Absence of sEVsCD73 enhances sensitivity to anti-PD-1 therapy by reversing immunosuppression.
- Circulating sEVsCD73 are associated with increased risk of lymph node metastasis and worse prognosis.
Conclusions:
- sEVsCD73 contribute to immunosuppression in HNSCC by modulating TAMs.
- sEVsCD73 represent a potential predictive biomarker for anti-PD-1 therapy response in HNSCC.
- Targeting sEVsCD73 may offer a novel therapeutic strategy for HNSCC.
