Journal
CELLULAR & MOLECULAR IMMUNOLOGY
Volume 19, Issue 11, Pages 1290-1301Publisher
CHIN SOCIETY IMMUNOLOGY
DOI: 10.1038/s41423-022-00926-6
Keywords
Tumor; Extracellular vesicles; PD-L1
Categories
Funding
- National Natural Science Foundation of China [82130053, 31970845, 31870876, 81971871, 81901571]
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PD-L1(+) tumor-derived extracellular vesicles (TEVs) cause resistance to anti-PD-L1 antibody therapy by decoying the antibody and being cleared by macrophages, resulting in insufficient blockade of tumor PD-L1.
PD-L1(+) tumor-derived extracellular vesicles (TEVs) cause systemic immunosuppression and possibly resistance to anti-PD-L1 antibody (alpha PD-L1) blockade. However, whether and how PD-L1(+) TEVs mediate alpha PD-L1 therapy resistance is unknown. Here, we show that PD-L1(+) TEVs substantially decoy alpha PD-L1 and that TEV-bound alpha PD-L1 is more rapidly cleared by macrophages, causing insufficient blockade of tumor PD-L1 and subsequent alpha PD-L1 therapy resistance. Inhibition of endogenous production of TEVs by Rab27a or Coro1a knockout reverses alpha PD-L1 therapy resistance. Either an increased alpha PD-L1 dose or macrophage depletion mediated by the clinical drug pexidartinib abolishes alpha PD-L1 therapy resistance. Moreover, in the treatment cycle with the same total treatment dose of alpha PD-L1, high-dose and low-frequency treatment had better antitumor effects than low-dose and high-frequency treatment, induced stronger antitumor immune memory, and eliminated alpha PD-L1 therapy resistance. Notably, in humanized immune system mice with human xenograft tumors, both increased alpha PD-L1 dose and high-dose and low-frequency treatment enhanced the antitumor effects of alpha PD-L1. Furthermore, increased doses of alpha PD-L1 and alpha PD-1 had comparable antitumor effects, but alpha PD-L1 amplified fewer PD-1(+) Treg cells, which are responsible for tumor hyperprogression. Altogether, our results reveal a TEV-mediated mechanism of alpha PD-L1-specific therapy resistance, thus providing promising strategies to improve alpha PD-L1 efficacy.
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