Polymeric structure and host Toll-like receptor 4 dictate immunogenicity of NY-ESO-1 antigen in vivo |
| |
Authors: | Liu Yanan Tian Xiaoli Leitner Wolfgang W Aldridge Michael E Zheng Junying Yu Zhiya Restifo Nicholas P Weiss Richard Scheiblhofer Sandra Xie Chong Sun Ren Cheng Genhong Zeng Gang |
| |
Affiliation: | Department of Urology, David Geffen School of Medicine at UCLA, Los Angeles, California 90095, USA. |
| |
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. |
| |
Keywords: | Antigen Cell Surface Receptor Dendritic Cells Toll-like Receptors (TLR) Tumor Immunology Vaccine Development Calreticulin Damage-associated Molecular Pattern Tumor-associated Antigen |
本文献已被 PubMed 等数据库收录! |