Curcumin Micelles Remodel Tumor Microenvironment and Enhance Vaccine Activity in an Advanced Melanoma Model

Mol Ther. 2016 Feb;24(2):364-374. doi: 10.1038/mt.2015.165. Epub 2015 Sep 3.

Abstract

Previously, we have reported a lipid-based Trp2 peptide vaccine for immunotherapy against melanoma. The suppressive immune microenvironment in the tumor is a major hurdle for an effective vaccine therapy. We hypothesized that curcumin (CUR) would remodel the tumor microenvironment to improve the vaccine activity. Curcumin-polyethylene glycol conjugate (CUR-PEG), an amphiphilic CUR-based micelle, was delivered intravenously (i.v.) to the tumor. Indeed, in the B16F10 tumor-bearing mice, the combination of CUR-PEG and vaccine treatment resulted in a synergistic antitumor effect (P < 0.001) compared to individual treatments. In the immune organs, the combination therapy significantly boosted in vivo cytotoxic T-lymphocyte response (41.0 ± 5.0% specific killing) and interferon-γ (IFN-γ) production (sevenfold increase). In the tumor microenvironment, the combination therapy led to significantly downregulated levels of immunosuppressive factors, such as decreased numbers of myeloid-derived suppressor cells and regulatory T cells (Treg) cells and declined levels of interleukin-6 and chemokine ligand 2-in correlation with increased levels of proinflammatory cytokines, including tumor necrosis factor-α and IFN-γ as well as an elevation in the CD8(+) T-cell population. The results indicated a distinct M2 to M1 phenotype switch in the treated tumors. Combining CUR-PEG and vaccine also dramatically downregulated the signal transducer and activator of transcription 3 pathway (76% reduction). Thus, we conclude that CUR-PEG is an effective agent to improve immunotherapy for advanced melanoma.

Publication types

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

MeSH terms

  • Administration, Intravenous
  • Animals
  • Antineoplastic Agents / administration & dosage*
  • Antineoplastic Agents / pharmacology
  • Cancer Vaccines / administration & dosage*
  • Cancer Vaccines / pharmacology
  • Curcumin / administration & dosage*
  • Curcumin / chemistry
  • Curcumin / pharmacology
  • Drug Synergism
  • Drug Therapy, Combination
  • Female
  • Gene Expression Regulation, Neoplastic / drug effects
  • Melanoma, Experimental / drug therapy*
  • Melanoma, Experimental / immunology
  • Mice
  • Micelles
  • Polyethylene Glycols / chemistry
  • Signal Transduction / drug effects
  • T-Lymphocytes, Cytotoxic / immunology
  • Tumor Microenvironment / drug effects*

Substances

  • Antineoplastic Agents
  • Cancer Vaccines
  • Micelles
  • Polyethylene Glycols
  • Curcumin