Clinical significance of PD-L1+ exosomes in plasma of Head and Neck Cancer patients

Purpose: The microenvironment of head and neck squamous cell carcinomas (HNSCCs) is highly immunosuppressive. HNSCCs expressing elevated levels of PD-L1 have especially poor outcome. Exosomes that carry PD-L1 and suppress T-cell functions have been isolated from plasma of patients with HNSCC. The potential contributions of PD-L1+ exosomes to immune suppression and disease activity are evaluated. Methods: Exosomes isolated from plasma of 40 HNSCC patients by size exclusion chromatography were captured on beads using anti-CD63 Abs, stained for PD-1 and PD-L1 and analyzed by flow cytometry. The percentages and mean fluorescence intensities (MFIs) of PD-L1+ and PD-1+ exosome/bead complexes were correlated with the patients' clinicopathological data. PD-L1high or PD-L1low exosomes were incubated with activated CD69+ human CD8+ T-cells ± PD-1 inhibitor. Changes in CD69 expression levels on T cells were measured. Patients' plasma was tested for soluble PD-L1 (sPD-L1) by ELISA. Results: Levels of PD-L1 carried by exosomes correlated with patients' disease activity, the UICC stage and the lymph node status (p= 0.0008-0.013). In contrast, plasma levels of sPD-L1 or exosome PD-1 levels did not correlate with any clinicopathological parameters. CD69 expression levels were inhibited (p<0.03) by co-incubation with PD-L1high but not by PD-L1low exosomes. Blocking of PD-L1+ exosome signaling to PD-1+ T cells attenuated immune suppression. Conclusions: PD-L1 levels on exosomes, but not levels of sPD-L1, associated correlate with disease progression in HNSCC patients. Circulating PD-L1+ exosomes emerge as useful metrics of disease and immune activity in HNSCC patients.

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