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In Vivo Immunogenicity Screening of Tumor-Derived Extracellular Vesicles by Flow Cytometry of Splenic T Cells
Published on: September 23, 2021
Tumor extracellular vesicles mediate anti-PD-L1 therapy resistance by decoying anti-PD-L1
Jiming Chen1, Jie Yang1, Wenhui Wang1
1Institute of Immunology, and Department of Orthopaedics of the Second Affiliated Hospital, Zhejiang University School of Medicine, 310058, Hangzhou, China.
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, high-dose and low-frequency treatment had better antitumor effects than low-dose and high-frequency treatment, induced stronger antitumor immune memory, and eliminated αPD-L1 therapy resistance. Notably, in humanized immune system mice with human xenograft tumors, both increased αPD-L1 dose and high-dose and low-frequency treatment enhanced the antitumor effects of αPD-L1. Furthermore, increased doses of αPD-L1 and αPD-1 had comparable antitumor effects, but αPD-L1 amplified fewer PD-1+ Treg cells, which are responsible for tumor hyperprogression. Altogether, our results reveal a TEV-mediated mechanism of αPD-L1-specific therapy resistance, thus providing promising strategies to improve αPD-L1 efficacy.
Insights
Tumor-derived extracellular vesicles (TEVs) carrying PD-L1 can cause resistance to anti-PD-L1 antibody therapy by trapping the antibody. Strategies like increasing antibody dose or altering treatment frequency can overcome this resistance.
Area of Science:
- Immunology
- Oncology
- Cell Biology
Background:
- PD-L1 expression on tumor cells and immune cells is a key mechanism of immune evasion in cancer.
- Anti-PD-L1 antibody (αPD-L1) therapy is a cornerstone of cancer immunotherapy, but resistance remains a significant challenge.
- Tumor-derived extracellular vesicles (TEVs) have been implicated in modulating the tumor microenvironment and immune responses.
Purpose of the Study:
- To investigate the role of PD-L1-positive TEVs in mediating resistance to αPD-L1 therapy.
- To elucidate the mechanisms by which PD-L1+ TEVs confer therapy resistance.
- To identify potential strategies to overcome αPD-L1 resistance mediated by TEVs.
Main Methods:
- Utilized knockout mouse models (Rab27a, Coro1a) to inhibit TEV production.
- Administered αPD-L1 therapy with varying doses and frequencies.
- Employed macrophage depletion using pexidartinib.
- Assessed antitumor effects and immune memory in humanized immune system mice with human xenograft tumors.
Main Results:
- PD-L1+ TEVs decoy αPD-L1, leading to rapid clearance of TEV-bound antibody by macrophages and insufficient blockade of tumor PD-L1.
- Inhibition of TEV production, increased αPD-L1 dose, or macrophage depletion reversed αPD-L1 resistance.
- High-dose, low-frequency αPD-L1 treatment demonstrated superior antitumor effects and immune memory compared to low-dose, high-frequency treatment.
- Increased αPD-L1 dose and high-dose, low-frequency treatment enhanced efficacy in humanized mice.
- αPD-L1 showed comparable antitumor effects to αPD-1 but amplified fewer immunosuppressive PD-1+ Treg cells.
Conclusions:
- PD-L1+ TEVs represent a novel mechanism of αPD-L1 therapy resistance by sequestering the antibody.
- Strategies targeting TEV production, increasing αPD-L1 dose, modulating macrophage activity, and optimizing treatment schedules can overcome this resistance.
- Findings provide a basis for developing improved immunotherapy regimens to enhance anti-PD-L1 efficacy in cancer patients.
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