Tumor extracellular vesicles mediate anti-PD-L1 therapy resistance by decoying anti-PD-L1.

ABSTRACT: PD-L1⁺ tumor-derived extracellular vesicles (TEVs) cause systemic immunosuppression and possibly resistance to anti-PD-L1 antibody (αPD-L1) blockade. However, whether and how PD-L1⁺ TEVs mediate αPD-L1 therapy resistance is unknown. Here, we show that PD-L1⁺ TEVs substantially decoy αPD-L1 and that TEV-bound αPD-L1 is more rapidly cleared by macrophages, causing insufficient blockade of tumor PD-L1 and subsequent αPD-L1 therapy resistance. Inhibition of endogenous production of TEVs by Rab27a or Coro1a knockout reverses αPD-L1 therapy resistance. Either an increased αPD-L1 dose or macrophage depletion mediated by the clinical drug pexidartinib abolishes αPD-L1 therapy resistance. Moreover, in the treatment cycle with the same total treatment dose of αPD-L1,

SUBMITTER: Chen J 

PROVIDER: S-EPMC9622748 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature