Circumventing Myeloid-Derived Suppressor Cell-Mediated Immunosuppression Using an Oxygen-Generated and -Economized Nanoplatform

ACS Appl Mater Interfaces. 2020 Dec 16;12(50):55723-55736. doi: 10.1021/acsami.0c18180. Epub 2020 Dec 4.

Abstract

The myeloid-derived suppressor cell (MDSC)-mediated immunosuppressive tumor microenvironment (TME), where tumor hypoxia counts for much, has greatly compromised the outcome of cancer immunotherapy. Here, we demonstrated a strategy for selectively clearing intratumoral MDSCs. Specifically, 2-[2-[2-chloro-3-[(1,3-dihydro-3,3-dimethyl-1-propyl-2H-indol-2-ylidene)ethylidene]-1-cyclohexen-1-yl]ethenyl]-3,3-dimethyl-1-propylindolium iodide (IR-780) and metformin (Met) were coloaded into mesoporous silica nanoparticles (MSNs) with CeO2 as the gatekeepers. Controlled release of cargos was achieved upon etching CeO2 with endogenous H2O2. Apart from the drug release, oxygen (O2) was also generated in this process. Importantly, the engagement of Met significantly inhibited mitochondrial respiration, thus working like an O2 economizer. Consequently, the populations and functions of tumor-infiltrated MDSCs were both dramatically reduced through selective alleviation of hypoxia at tumor sites, thus contributing to boosted immune responses. Additionally, the accumulated O2 enhanced IR780-mediated photodynamic therapy, which synergistically strengthened the antitumor efficacy of the platform. To the best of our knowledge, this is the first time to employ an O2-generated and -economized nanoplatform for selectively anergizing MDSC-mediated immunosuppression. We expect that this strategy will shed new light on the clinical cancer immunotherapy treatment.

Keywords: hypoxia; myeloid-derived suppressor cells; nanoparticles; oxygen economization; oxygen generation.

MeSH terms

  • Animals
  • Antineoplastic Agents / chemistry*
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Cerium / chemistry*
  • Female
  • Hydrogen Peroxide / chemistry
  • Indoles / chemistry*
  • Indoles / metabolism
  • Indoles / pharmacology
  • Lymphocyte Activation / drug effects
  • Metformin / chemistry*
  • Metformin / metabolism
  • Metformin / pharmacology
  • Mice
  • Mice, Inbred C57BL
  • Mitochondria / drug effects
  • Mitochondria / metabolism
  • Myeloid-Derived Suppressor Cells / cytology
  • Myeloid-Derived Suppressor Cells / metabolism
  • Nanostructures / chemistry*
  • Neoplasms / drug therapy
  • Neoplasms / pathology
  • Oxygen / chemistry
  • Oxygen / metabolism*
  • Reactive Oxygen Species / metabolism
  • Silicon Dioxide / chemistry
  • T-Lymphocytes, Cytotoxic / cytology
  • T-Lymphocytes, Cytotoxic / metabolism
  • Tumor Microenvironment

Substances

  • 2-(2-(2-chloro-3-((1,3-dihydro-3,3-dimethyl-1-propyl-2H-indol-2-ylidene)ethylidene)-1-cyclohexen-1-yl)ethenyl)-3,3-dimethyl-1-propylindolium
  • Antineoplastic Agents
  • Indoles
  • Reactive Oxygen Species
  • Cerium
  • ceric oxide
  • Silicon Dioxide
  • Metformin
  • Hydrogen Peroxide
  • Oxygen