title: Adjuvant engineering for cancer immunotherapy: Development of a synthetic TLR2 ligand with increased cell adhesion.
abstract: The development of effective immunoadjuvants for tumor immunotherapy is of fundamental importance. The use of Mycobacterium bovis bacillus Calmette-Guérin cell wall skeleton (BCG-CWS) in tumor immunotherapy has been examined in various clinical applications. Because BCG-CWS is a macromolecule that cannot be chemically synthesized, the development of an alternative synthetic molecule is necessary to ensure a constant supply of adjuvant. In the present study, a new adjuvant was designed based on the structure of macrophage-activating lipopeptide (MALP)-2, which is a Toll-like receptor (TLR)-2 ligand similar to BCG-CWS. Macrophage-activating lipopeptide-2, [S-(2,3-bispalmitoyloxypropyl)Cys (P2C) - GNNDESNISFKEK], originally identified in a Mycoplasma species, is a lipopeptide that can be chemically synthesized. A MALP-2 peptide was substituted with a functional motif, RGDS, creating a novel molecule named P2C-RGDS. RGDS was selected because its sequence constitutes an integrin-binding motif and various integrins are expressed in immune cells including dendritic cells (DCs). Thus, this motif adds functionality to the ligand. P2C-RGDS activated DCs and splenocytes more efficiently than MALP-2 over short incubation times in vitro, and the RGDS motif contributed to their activation. Furthermore, P2C-RGDS showed higher activity than MALP-2 in inducing migration of DCs to draining lymph node, and in inhibiting tumor growth in vivo. This process of designing and developing synthetic adjuvants has been named "adjuvant engineering," and the evaluation and improvement of P2C-RGDS constitutes a first step in the development of stronger synthetic adjuvants in the future.
authors.affiliation: Department of Molecular Genetics, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, Japan. akazawa-ta@mc.pref.osaka.jp
authors.forename: Takashi
authors.initials: T
authors.lastname: Akazawa
authors.forename: Norimitsu
authors.initials: N
authors.lastname: Inoue
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Shime
authors.forename: Ken
authors.initials: K
authors.lastname: Kodama
authors.forename: Misako
authors.initials: M
authors.lastname: Matsumoto
authors.forename: Tsukasa
authors.initials: T
authors.lastname: Seya
mesh_terms: D000276:Adjuvants, Immunologic / Q000737:chemistry / Q000627:therapeutic use; D000595:Amino Acid Sequence; D000818:Animals; D001500:BCG Vaccine / Q000627:therapeutic use; D002448:Cell Adhesion / Q000276:immunology / Q000502:physiology; D064987:Cell- and Tissue-Based Therapy / Q000379:methods; D003713:Dendritic Cells / Q000276:immunology; D007167:Immunotherapy / Q000379:methods*; D008024:Ligands; D055666:Lipopeptides / Q000627:therapeutic use; D008198:Lymph Nodes / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009369:Neoplasms / Q000276:immunology*; D009842:Oligopeptides / Q000737:chemistry / Q000276:immunology; D023822:Tissue Engineering / Q000379:methods*; D051194:Toll-Like Receptor 1 / Q000172:deficiency / Q000235:genetics; D051195:Toll-Like Receptor 2 / Q000276:immunology*
chemical_list: D000276:Adjuvants, Immunologic; D001500:BCG Vaccine; D008024:Ligands; D055666:Lipopeptides; D009842:Oligopeptides; D051194:Toll-Like Receptor 1; D051195:Toll-Like Receptor 2; C046617:arginyl-glycyl-aspartyl-serine