1. Academic Validation
  2. TLR7/8-agonist-loaded nanoparticles promote the polarization of tumour-associated macrophages to enhance cancer immunotherapy

TLR7/8-agonist-loaded nanoparticles promote the polarization of tumour-associated macrophages to enhance cancer immunotherapy

  • Nat Biomed Eng. 2018 Aug;2(8):578-588. doi: 10.1038/s41551-018-0236-8.
Christopher B Rodell 1 Sean P Arlauckas 1 Michael F Cuccarese 1 Christopher S Garris 1 2 Ran Li 1 Maaz S Ahmed 1 Rainer H Kohler 1 Mikael J Pittet 1 Ralph Weissleder 3 4
Affiliations

Affiliations

  • 1 Center for Systems Biology, Massachusetts General Hospital Research Institute, Boston, MA, USA.
  • 2 Graduate Program in Immunology, Harvard Medical School, Boston, MA, USA.
  • 3 Center for Systems Biology, Massachusetts General Hospital Research Institute, Boston, MA, USA. [email protected]
  • 4 Department of Systems Biology, Harvard Medical School, Boston, MA, USA. [email protected]
Abstract

Tumour-associated macrophages are abundant in many cancers, and often display an immune-suppressive M2-like phenotype that fosters tumour growth and promotes resistance to therapy. Yet, macrophages are highly plastic and can also acquire an anti-tumorigenic M1-like phenotype. Here, we show that R848, an agonist of the toll-like receptors TLR7 and TLR8 identified in a morphometric-based screen, is a potent driver of the M1 phenotype in vitro and that R848-loaded β-cyclodextrin nanoparticles (CDNP-R848) lead to efficient drug delivery to tumour-associated macrophages in vivo. As a monotherapy, the administration of CDNP-R848 in multiple tumour models in mice altered the functional orientation of the tumour immune microenvironment towards an M1 phenotype, leading to controlled tumour growth and protecting the Animals against tumour rechallenge. When used in combination with the immune checkpoint inhibitor anti-PD-1, we observed improved immunotherapy response rates, including in a tumour model resistant to anti-PD-1 therapy alone. Our findings demonstrate the ability of rationally engineered drug-nanoparticle combinations to efficiently modulate tumour-associated macrophages for Cancer Immunotherapy.

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