title: Nanoparticle-delivered transforming growth factor-β siRNA enhances vaccination against advanced melanoma by modifying tumor microenvironment.
abstract: Achievement of potent immunoresponses against self/tumor antigens and effective therapeutic outcome against advanced tumors remain major challenges in cancer immunotherapy. The specificity and efficiency of two nanoparticle-based delivery systems, lipid-calcium-phosphate (LCP) nanoparticle (NP) and liposome-protamine-hyaluronic acid (LPH) NP, provide us an opportunity to address both challenges. A mannose-modified LCP NP delivered both tumor antigen (Trp 2 peptide) and adjuvant (CpG oligonucleotide) to the dendritic cells and elicited a potent, systemic immune response regardless of the existence or the stage of tumors in the host. This vaccine was less effective, however, against later stage B16F10 melanoma in a subcutaneous syngeneic model. Mechanistic follow-up studies suggest that elevated levels of immune-suppressive cytokines within the tumor microenvironment, such as TGF-β, might be responsible. We strategically augment the efficacy of LCP vaccine on an advanced tumor by silencing TGF-β in tumor cells. The delivery of siRNA using LPH NP resulted in about 50% knockdown of TGF-β in the late stage tumor microenvironment. TGF-β down-regulation boosted the vaccine efficacy and inhibited tumor growth by 52% compared with vaccine treatment alone, as a result of increased levels of tumor infiltrating CD8+ T cells and decreased level of regulatory T cells. Combination of systemic induction of antigen-specific immune response with LCP vaccine and targeted modification of tumor microenvironment with LPH NP offers a flexible and powerful platform for both mechanism study and immunotherapeutic strategy development.
authors.affiliation: 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 27599, United States.
authors.forename: Zhenghong
authors.initials: Z
authors.lastname: Xu
authors.forename: Yuhua
authors.initials: Y
authors.lastname: Wang
authors.forename: Lu
authors.initials: L
authors.lastname: Zhang
authors.forename: Leaf
authors.initials: L
authors.lastname: Huang
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002130:Calcium Phosphates / Q000737:chemistry; D049109:Cell Proliferation; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology; D018450:Disease Progression; D015536:Down-Regulation / Q000276:immunology; D004337:Drug Carriers / Q000737:chemistry; D005260:Female; D006820:Hyaluronic Acid / Q000737:chemistry; D008546:Melanoma, Experimental / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D051379:Mice; D053758:Nanoparticles / Q000737:chemistry*; D011479:Protamines / Q000737:chemistry; D034741:RNA, Small Interfering / Q000737:chemistry* / Q000235:genetics; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D016212:Transforming Growth Factor beta / Q000172:deficiency* / Q000235:genetics*; D059016:Tumor Microenvironment / Q000235:genetics / Q000276:immunology*; D014611:Vaccination / Q000379:methods*
chemical_list: D000951:Antigens, Neoplasm; D002130:Calcium Phosphates; D016207:Cytokines; D004337:Drug Carriers; D011479:Protamines; D034741:RNA, Small Interfering; D016212:Transforming Growth Factor beta; D006820:Hyaluronic Acid; C020243:calcium phosphate