Tumor extracellular vesicles mediate anti-PD-L1 therapyresistance by decoying anti-PD-L1

摘要

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 mediateαPD-L1 therapy resistance is unknown.Here,we show that PD-L1+TEVs substantially decoyαPD-L1 and that TEV-boundαPD-L1 is more rapidly cleared by macrophages,causing insufficient blockade of tumor PD-L1 and subsequentαPD-L1 therapy resistance.Inhibition of endogenous production of TEVs by Rab27a or Coro1a knockout reversesαPD-L1 therapy resistance.Either an increasedαPD-L1 dose or macrophage depletion mediated by the clinical drug pexidartinib abolishesαPD-L1 therapy resistance.Moreover,in the treatment cycle with the same total treatment dose ofαPD-L1,high-dose and low-frequency treatment had better antitumor effects than low-dose and highfrequency treatment,induced stronger antitumor immune memory,and eliminatedαPD-L1 therapy resistance.Notably,in humanized immune system mice with human xenograft tumors,both increasedαPD-L1 dose and high-dose and low-frequency treatment enhanced the antitumor effects ofαPD-L1.Furthermore,increased doses ofαPD-L1 andαPD-1 had comparable antitumor effects,butαPD-L1 amplified fewer PD-1+Treg cells,which are responsible for tumor hyperprogression.Altogether,our results reveal a TEV-mediated mechanism ofαPD-L1-specific therapy resistance,thus providing promising strategies to improveαPD-L1 efficacy.