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Polymeric Structure and Host Toll-like Receptor 4 Dictate Immunogenicity of NY-ESO-1 Antigen in Vivo

2011; Elsevier BV; Volume: 286; Issue: 43 Linguagem: Inglês

10.1074/jbc.m111.280123

1083-351X

Yanan Liu, Xiaoli Tian, Wolfgang W. Leitner, Michael E. Aldridge, Junying Zheng, Zhiya Yu, Nicholas P. Restifo, Richard Weiss, Sandra Scheiblhofer, Chong Xie, Ren Sun, Genhong Cheng, Gang Zeng,

T-cell and B-cell Immunology

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.