Boosting anti-PD-1 therapy with metformin-loaded macrophage-derived microparticles

Nat Commun. 2021 Jan 19;12(1):440. doi: 10.1038/s41467-020-20723-x.

Abstract

The main challenges for programmed cell death 1(PD-1)/PD-1 ligand (PD-L1) checkpoint blockade lie in a lack of sufficient T cell infiltration, tumor immunosuppressive microenvironment, and the inadequate tumor accumulation and penetration of anti-PD-1/PD-L1 antibody. Resetting tumor-associated macrophages (TAMs) is a promising strategy to enhance T-cell antitumor immunity and ameliorate tumor immunosuppression. Here, mannose-modified macrophage-derived microparticles (Man-MPs) loading metformin (Met@Man-MPs) are developed to efficiently target to M2-like TAMs to repolarize into M1-like phenotype. Met@Man-MPs-reset TAMs remodel the tumor immune microenvironment by increasing the recruitment of CD8+ T cells into tumor tissues and decreasing immunosuppressive infiltration of myeloid-derived suppressor cells and regulatory T cells. More importantly, the collagen-degrading capacity of Man-MPs contributes to the infiltration of CD8+ T cells into tumor interiors and enhances tumor accumulation and penetration of anti-PD-1 antibody. These unique features of Met@Man-MPs contribute to boost anti-PD-1 antibody therapy, improving anticancer efficacy and long-term memory immunity after combination treatment. Our results support Met@Man-MPs as a potential drug to improve tumor resistance to anti-PD-1 therapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology*
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use
  • Cell Line, Tumor
  • Cell-Derived Microparticles / immunology*
  • Drug Carriers / pharmacology*
  • Drug Synergism
  • Female
  • Humans
  • Immune Checkpoint Inhibitors / pharmacology
  • Immune Checkpoint Inhibitors / therapeutic use
  • Immunologic Memory
  • Male
  • Metformin / pharmacology
  • Metformin / therapeutic use
  • Mice
  • Neoplasms / drug therapy*
  • Neoplasms / immunology
  • Programmed Cell Death 1 Receptor / antagonists & inhibitors
  • Programmed Cell Death 1 Receptor / immunology
  • RAW 264.7 Cells
  • Tumor Escape / drug effects
  • Tumor Escape / immunology
  • Tumor Microenvironment / drug effects
  • Tumor Microenvironment / immunology
  • Tumor-Associated Macrophages / drug effects
  • Tumor-Associated Macrophages / immunology
  • Xenograft Model Antitumor Assays

Substances

  • Drug Carriers
  • Immune Checkpoint Inhibitors
  • PDCD1 protein, human
  • Programmed Cell Death 1 Receptor
  • Metformin