title: Polymeric structure and host Toll-like receptor 4 dictate immunogenicity of NY-ESO-1 antigen in vivo.
abstract: In search of intrinsic factors that contribute to the distinctively strong immunogenicity of a non-mutated cancer/testis antigen, we found that NY-ESO-1 forms polymeric structures through disulfide bonds. NY-ESO-1 binding to immature dendritic cells was dependent on its polymeric structure and involved Toll-like receptor-4 (TLR4) on the surface of immature dendritic cells in mouse and human. Gene gun-delivered plasmid encoding the wild-type NY-ESO-1 readily induced T cell-dependent antibody (Ab) responses in wild-type C57BL/10 mice but not TLR4-knock-out C57BL/10ScNJ mice. Disrupting polymeric structures of NY-ESO-1 by cysteine-to-serine (Cys-to-Ser) substitutions lead to diminished immunogenicity and altered TLR4-dependence in the induced Ab response. To demonstrate its adjuvant effect, NY-ESO-1 was fused with a major mugwort pollen allergen Art v 1 and a tumor-associated antigen, carbonic anhydrase 9. Plasmid DNA vaccines encoding the fusion genes generated robust immune responses against otherwise non-immunogenic targets in mice. Polymeric structure and TLR4 may play important roles in rendering NY-ESO-1 immunogenic and thus serve as a potent molecular adjuvant. NY-ESO-1 thus represents the first example of a cancer/testis antigen that is a also damage-associated molecular pattern.
authors: Department of Urology, David Geffen School of Medicine at UCLA, Los Angeles, California 90095, USA.
authors: Yanan
authors: Y
authors: Liu
authors: Xiaoli
authors: X
authors: Tian
authors: Wolfgang W
authors: WW
authors: Leitner
authors: Michael E
authors: ME
authors: Aldridge
authors: Junying
authors: J
authors: Zheng
authors: Zhiya
authors: Z
authors: Yu
authors: Nicholas P
authors: NP
authors: Restifo
authors: Richard
authors: R
authors: Weiss
authors: Sandra
authors: S
authors: Scheiblhofer
authors: Chong
authors: C
authors: Xie
authors: Ren
authors: R
authors: Sun
authors: Genhong
authors: G
authors: Cheng
authors: Gang
authors: G
authors: Zeng
mesh_terms: D000818:Animals; D000912:Antibodies, Neoplasm / Q000276:immunology; D000917:Antibody Formation / Q000235:genetics / Q000276:immunology; D000951:Antigens, Neoplasm / Q000235:genetics / Q000276:immunology*; D019496:Cancer Vaccines / Q000235:genetics / Q000276:immunology*; D045744:Cell Line, Tumor; D003713:Dendritic Cells / Q000276:immunology*; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D011485:Protein Binding / Q000235:genetics / Q000276:immunology; D055503:Protein Multimerization / Q000235:genetics / Q000276:immunology*; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000276:immunology*; D019444:Vaccines, DNA / Q000235:genetics / Q000276:immunology*
chemical_list: D000912:Antibodies, Neoplasm; D000951:Antigens, Neoplasm; C104948:CTAG1B protein, human; D019496:Cancer Vaccines; D008565:Membrane Proteins; C495345:TLR4 protein, human; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D019444:Vaccines, DNA