Targeting the tumor-draining lymph node with adjuvanted nanoparticles reshapes the anti-tumor immune response

Susan N. Thomas, Efthymia Vokali, Amanda W. Lund, Jeffrey A. Hubbell, Melody A. Swartz

Research output: Contribution to journalArticle

152 Scopus citations

Abstract

Accumulating evidence implicates the tumor-draining lymph node (TDLN) in tumor-induced immune escape, as it drains regulatory molecules and leukocytes from the tumor microenvironment. We asked whether targeted delivery of adjuvant to the TDLN, presumably already bathed in tumor antigens, could promote anti-tumor immunity and hinder tumor growth. To this end, we used 30nm polymeric nanoparticles (NPs) that effectively target dendritic cells (DCs, CD11c+) within the lymph node (LN) after intradermal administration. These NPs accumulated within the TDLN when administered in the limb ipsilateral (i.l.) to the tumor or in the non-TDLN when administered in the contralateral (c.l.) limb. Incorporating the adjuvants CpG or paclitaxel into the NPs (CpG-NP and PXL-NP) induced DC maturation invitro. When administered daily i.l. and thus targeting the TDLN of a B16-F10 melanoma, adjuvanted NPs induced DC maturation within the TDLN and reshaped the CD4+ T cell distribution within the tumor towards a Th1 (CXCR3+) phenotype. Importantly, this also led to an increase in the frequency of antigen-specific CD8+ T cells within the tumor. This correlated with slowed tumor growth, in contrast to unhindered tumor growth after c.l. delivery of adjuvanted NPs (targeting a non-TDLN) or i.l. delivery of free adjuvant. CpG-NP treatment in the i.l. limb also was associated with an increase in CD8+/CD4+ T cell ratios and frequencies of activated (CD25+) CD8+ T cells within the TDLN whereas PXL-NP treatment reduced the frequency of regulatory T (FoxP3+ CD4+) cells in the TDLN. Together, these data implicate the TDLN as a delivery target for adjuvant therapy of solid tumors.

Original languageEnglish (US)
Pages (from-to)814-824
Number of pages11
JournalBiomaterials
Volume35
Issue number2
DOIs
StatePublished - Jan 1 2014

Keywords

  • Drug delivery
  • Immunomodulation
  • Immunotherapy
  • Sentinel lymph node
  • Tumor-draining lymph node

ASJC Scopus subject areas

  • Bioengineering
  • Ceramics and Composites
  • Biophysics
  • Biomaterials
  • Mechanics of Materials

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