Nanoparticle-Conjugate TLR7/8 Agonist Localized Immunotherapy Provokes Safe Antitumoral Responses

Lutz Nuhn, Stefaan De Koker, Sandra Van Lint, Zifu Zhong, João Portela Catani, Francis Combes, Kim Deswarte, Yupeng Li, Bart N. Lambrecht, Stefan Lienenklaus, Niek N. Sanders, Sunil A. David, Jan Tavernier, Bruno G. De Geest

Research output: Contribution to journalArticlepeer-review

42 Scopus citations

Abstract

Localized therapeutic modalities that subvert the tumor microenvironment from immune-suppressive to pro-immunogenic can elicit systemic antitumor immune responses that induce regression of directly treated as well as nontreated distal tumors. A key toward generating robust antitumor T cell responses is the activation of dendritic cells (DCs) in the tumor microenvironment. Treatment with agonists triggering various pattern recognition receptors is very efficient to activate DCs, yet suffers from the induction of serious immune-related adverse effects, which is closely linked to their unfavorable PK/PD profile causing systemic immune activation and cytokine release. Here, it is reported that nanoparticle conjugation of a highly potent TLR7/8 agonist restricts immune activation to the tumor bed and its sentinel lymph nodes without hampering therapeutic antitumor efficacy. On a mechanistic level, it is confirmed that localized treatment with a nanoparticle-conjugated TLR7/8 agonist leads to potent activation of DCs in the sentinel lymph nodes and promotes proliferation of tumor antigen-specific CD8 T cells. Furthermore, therapeutic improvement upon combination with anti-PDL1 checkpoint inhibition and Flt3L, a growth factor that expands and mobilizes DCs from the bone marrow, is demonstrated. The findings provide a rational base for localized tumor engineering by nanomedicine strategies that provide spatial control over immune-activation.

Original languageEnglish (US)
Article number1803397
JournalAdvanced Materials
Volume30
Issue number45
DOIs
StatePublished - Nov 8 2018

Bibliographical note

Funding Information:
L.N., S.D.K., and S.V.L. contributed equally to this work. L.N. acknowledges the FWO-Flanders, the CRIG, and the Alexander-von-Humboldt Foundation for funding. B.G.D.G. acknowledges the FWO Flanders, Ghent University (BOF-GOA), and the Stichting tegen Kanker for funding. J.T. acknowledges ERC Advanced Grant CYRE (No. 340941) and FWO grant (No. G009614N). Moreover, the authors thank Maria Kokkinopoulou and Ingo Lieberwirth for the transmission electron microscopy images of the nanogels.

Publisher Copyright:
© 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

Keywords

  • TLR agonist
  • cancer
  • immune-engineering
  • nanoparticles

Fingerprint Dive into the research topics of 'Nanoparticle-Conjugate TLR7/8 Agonist Localized Immunotherapy Provokes Safe Antitumoral Responses'. Together they form a unique fingerprint.

Cite this