Myeloid Cell-Targeted Nanocarriers Efficiently Inhibit Cellular Inhibitor of Apoptosis for Cancer Immunotherapy

Cell Chem Biol. 2020 Jan 16;27(1):94-104.e5. doi: 10.1016/j.chembiol.2019.12.007. Epub 2020 Jan 2.

Abstract

Immune-checkpoint blockers can promote sustained clinical responses in a subset of cancer patients. Recent research has shown that a subpopulation of tumor-infiltrating dendritic cells functions as gatekeepers, sensitizing tumors to anti-PD-1 treatment via production of interleukin-12 (IL-12). Hypothesizing that myeloid cell-targeted nanomaterials could be used to deliver small-molecule IL-12 inducers, we performed high-content image-based screening to identify the most efficacious small-molecule compounds. Using one lead candidate, LCL161, we created a myeloid-targeted nanoformulation that induced IL-12 production in intratumoral myeloid cells in vivo, slowed tumor growth as a monotherapy, and had no significant systemic toxicity. These results pave the way for developing combination immunotherapeutics by harnessing IL-12 production for immunostimulation.

Keywords: cancer; dendritic cells; drug delivery; high-content drug screening; immunotherapy; interleukin-12; nanoparticle.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Alkynes / chemistry
  • Alkynes / pharmacology*
  • Animals
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects*
  • Cell Line, Tumor
  • Colonic Neoplasms / metabolism
  • Colonic Neoplasms / pathology
  • Colonic Neoplasms / therapy*
  • Dendritic Cells
  • Drug Carriers / chemistry
  • Drug Evaluation, Preclinical
  • Immunotherapy*
  • Interleukin-12 / biosynthesis
  • Mice
  • Myeloid Cells / drug effects*
  • Myeloid Cells / metabolism
  • Myeloid Cells / pathology
  • Nanoparticles / chemistry
  • Oligopeptides / chemistry
  • Oligopeptides / pharmacology*
  • Small Molecule Libraries / chemistry
  • Small Molecule Libraries / pharmacology*
  • Thiazoles / chemistry
  • Thiazoles / pharmacology*

Substances

  • Alkynes
  • Antineoplastic Agents
  • Drug Carriers
  • LCL161
  • N,N'-(2,2'-(hexa-2,4-diyne-1,6-diylbis(oxy))bis(2,3-dihydro-1H-indene-2,1-diyl))bis(1-(2-cyclohexyl-2-(2-(methylamino)propanamido)acetyl)pyrrolidine-2-carboxamide)
  • Oligopeptides
  • Small Molecule Libraries
  • Thiazoles
  • Interleukin-12