Polymeric nanoparticles encapsulating novel TLR7/8 agonists as immunostimulatory adjuvants for enhanced cancer immunotherapy

Hyunjoon Kim, Lin Niu, Peter Larson, Tamara A. Kucaba, Katherine A. Murphy, Britnie R. James, David M Ferguson, Thomas S Griffith, Jayanth Panyam

Research output: Contribution to journalArticlepeer-review

96 Scopus citations

Abstract

Cytotoxic T lymphocytes (CTLs) play a major role in cancer immunotherapy because of their ability to directly kill tumor cells and secrete tumor suppressive cytokines. Anticancer vaccines aim to provoke tumor-specific CTL responses, which require activation of antigen presenting cells (APCs) including dendritic cells (DCs) and macrophages. Therefore, a potent immunostimulatory adjuvant capable of activating APCs is an essential component of anticancer vaccines. In this study, we introduce novel TLR 7/8 bi-specific agonists that significantly enhance cytokine secretion compared to TLR7 mono-selective compounds. Encapsulation of these TLR 7/8 agonists in poly(lactide-co-glycolide) (PLGA) nanoparticles increased the co-stimulatory molecule expression and antigen presentation via MHC I by DCs compared to the soluble agonist. When administered subcutaneously, these nanoparticles migrated to draining lymph node and triggered DC activation and expansion. This lead to expansion of antigen-specific CD8 T cells and enhanced CTL response, which resulted in significant prophylactic and therapeutic efficacy in melanoma, bladder and renal cell carcinoma tumor models. Importantly, our studies demonstrate significant reductions in systemic metastasis with the nanoparticle vaccine. Our results suggest novel TLR 7/8 agonist-encapsulated nanoparticles are potent immunostimulatory adjuvants for cancer immunotherapy.

Original languageEnglish (US)
Pages (from-to)38-53
Number of pages16
JournalBiomaterials
Volume164
DOIs
StatePublished - May 2018

Bibliographical note

Funding Information:
We thank John Oja and Guillermo Marques in the University Imaging Centers (University of Minnesota) for confocal microscopy training. TEM and SEM imaging was performed with the assistance of Han Seung Lee in the Characterization Facility (University of Minnesota), which receives partial support from NSF through the MRSEC program. This work was supported by the Grant in aid program, University of Minnesota (J.P.), GAP award (J.P.), Masonic Cancer Center, University of Minnesota (T.S.G.), the Prostate and Urological Cancer Translational Working Group (T.S.G.), and the Randy Shaver Cancer Research & Community Fund (J.P., T.S.G., D.M.F.)

Funding Information:
We thank John Oja and Guillermo Marques in the University Imaging Centers (University of Minnesota) for confocal microscopy training. TEM and SEM imaging was performed with the assistance of Han Seung Lee in the Characterization Facility (University of Minnesota), which receives partial support from NSF through the MRSEC program. This work was supported by the Grant in aid program, University of Minnesota (J.P.), GAP award (J.P.), Masonic Cancer Center, University of Minnesota (T.S.G.), the Prostate and Urological Cancer Translational Working Group (T.S.G.), and the Randy Shaver Cancer Research & Community Fund (J.P., T.S.G., D.M.F.)

Publisher Copyright:
© 2018

Keywords

  • Cancer vaccine
  • Immunotherapy
  • Nanoparticle
  • TLR7/8 agonist

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