Biochemical and biophysical research communications · 2026
Exosomes derived from M2-polarized tumor-associated macrophages contribute to immune escape in cervical cancer.
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Weng Xiaoxue, Zeng Chunyan, Lv Jiajin, Huang Fengyan, You Zhenjun, Hu Anquan, Liang Jin, Fu Jia
Аннотация
BACKGROUND: Tumor-associated macrophages (TAMs), particularly those polarized toward an M2-like phenotype, are major contributors to the immunosuppressive microenvironment in cervical cancer. Although soluble mediators such as IL-10 and TGF-β have been well characterized, the role of macrophage-derived exosomes in regulating immune checkpoint expression on tumor cells remains unclear.
METHODS: Exosomes were isolated from IL-4-polarized RAW264.7 macrophages and applied to HPV-positive TC-1 murine cervical cancer cells. PD-L1 expression was evaluated by quantitative PCR and flow cytometry. Functional impacts on antigen-specific CD8+ T cells were assessed using co-culture cytotoxicity assays and measurement of effector cytokines. The dependency on PD-L1 was determined through Cd274 knockdown. In vivo experiments were performed in a syngeneic TC-1 tumor model with intratumoral exosome administration and anti-PD-1 treatment.
RESULTS: TAM-derived exosomes were efficiently internalized by tumor cells and induced significant upregulation of PD-L1 at both mRNA and protein levels without affecting cell viability. This led to impaired CD8+ T cell-mediated killing and reduced secretion of IFN-γ, CXCL9, and CXCL10. The immunosuppressive effect was abolished in Cd274-deficient tumor cells and reversed by anti-PD-1 only in the presence of PD-L1. In mice, TAM exosomes promoted tumor growth, decreased CD8+ T cell infiltration, and attenuated the efficacy of anti-PD-1 therapy.
CONCLUSION: TAM-derived exosomes drive PD-L1-dependent immune evasion in cervical cancer. Targeting this myeloid exosome-tumor signaling axis represents a promising strategy to overcome resistance to immune checkpoint blockade.
METHODS: Exosomes were isolated from IL-4-polarized RAW264.7 macrophages and applied to HPV-positive TC-1 murine cervical cancer cells. PD-L1 expression was evaluated by quantitative PCR and flow cytometry. Functional impacts on antigen-specific CD8+ T cells were assessed using co-culture cytotoxicity assays and measurement of effector cytokines. The dependency on PD-L1 was determined through Cd274 knockdown. In vivo experiments were performed in a syngeneic TC-1 tumor model with intratumoral exosome administration and anti-PD-1 treatment.
RESULTS: TAM-derived exosomes were efficiently internalized by tumor cells and induced significant upregulation of PD-L1 at both mRNA and protein levels without affecting cell viability. This led to impaired CD8+ T cell-mediated killing and reduced secretion of IFN-γ, CXCL9, and CXCL10. The immunosuppressive effect was abolished in Cd274-deficient tumor cells and reversed by anti-PD-1 only in the presence of PD-L1. In mice, TAM exosomes promoted tumor growth, decreased CD8+ T cell infiltration, and attenuated the efficacy of anti-PD-1 therapy.
CONCLUSION: TAM-derived exosomes drive PD-L1-dependent immune evasion in cervical cancer. Targeting this myeloid exosome-tumor signaling axis represents a promising strategy to overcome resistance to immune checkpoint blockade.