Curcumin Micelles Remodel Tumor Microenvironment and Enhance Vaccine Activity in an Advanced Melanoma Model.
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.
Division of Molecular Pharmaceutics, Center for Nanotechnology in Drug Delivery, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA; School of Pharmacy, Huazhong University of Science and Technology, Wuhan, China.
Yao
Y
Lu
Division of Molecular Pharmaceutics, Center for Nanotechnology in Drug Delivery, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
Lei
L
Miao
Division of Molecular Pharmaceutics, Center for Nanotechnology in Drug Delivery, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
Yuhua
Y
Wang
Division of Molecular Pharmaceutics, Center for Nanotechnology in Drug Delivery, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
Zhenghong
Z
Xu
Division of Molecular Pharmaceutics, Center for Nanotechnology in Drug Delivery, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
Yi
Y
Zhao
Center for Bioengineering, State Key Laboratory for Chemical Engineering, Zhejiang University, Hangzhou, China.
Youqing
Y
Shen
School of Pharmacy, Huazhong University of Science and Technology, Wuhan, China. Electronic address: gyxiang1968@hotmail.com.
Guangya
G
Xiang
Division of Molecular Pharmaceutics, Center for Nanotechnology in Drug Delivery, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA. Electronic address: leafh@unc.edu.
Leaf
L
Huang
D061605:Administration, Intravenous; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000494:pharmacology; D019496:Cancer Vaccines / Q000008:administration & dosage* / Q000494:pharmacology; D003474:Curcumin / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D008546:Melanoma, Experimental / Q000188:drug therapy* / Q000276:immunology; D051379:Mice; D008823:Micelles; D011092:Polyethylene Glycols / Q000737:chemistry; D015398:Signal Transduction / Q000187:drug effects; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D059016:Tumor Microenvironment / Q000187:drug effects*
D000970:Antineoplastic Agents; D019496:Cancer Vaccines; D008823:Micelles; D011092:Polyethylene Glycols; D003474:Curcumin