Figure 1. Mechanisms of Exosome PD-L1 Mediated Immunosuppression.
PD-L1+ exosomes have been found to impart an immunosuppressive phenotype through both direct and indirect mechanisms. In general, exosomes form from the inward budding of vesicles within the multivesicular body (MVB). They are then released extracellularly through the function of Rab27 and nSMase2. In the direct mechanism (left panel), PD-L1 on the surface of tumor-derived exosomes binds directly to PD-1 on the surface of T-cells, inhibiting effector function and release of pro-inflammatory cytokines IFN-γ, IL-2, and granzyme B. In the indirect mechanism (middle panel), tumor-derived exosomes bind to a toll-like receptor (TLR) on the surface of a secondary cell type, namely myeloid cells, to induce PD-L1 expression which then binds to PD-1+ T cells and inhibits effector function. Lastly, exosomal PD-L1 has been implicated as a mechanism of resistance in immunotherapy (right panel). Specifically, PD-L1+ exosomes are thought to either bind to anti-PD-L1 mAb leaving tumor PD-L1 exposed or PD-L1+ exosomes bind directly to PD-1 on effector T cells despite mAb treatment. In both scenarios, the blocking effect of the antibody is negated allowing for continued PD-L1 mediated immunosuppression.