Liposomal Antitumor Vaccines Targeting Mucin 1 Elicit a Lipid‐Dependent Immunodominant Response

• Published in: Chemistry, an Asian journal an Asian journal, 2019-06, Vol.14 (12), p.2116-2121
• Main Authors: Du, Jing‐Jing, Zou, Shi‐Yao, Chen, Xiang‐Zhao, Xu, Wen‐Bo, Wang, Chang‐Wei, Zhang, Lian, Tang, Yuan‐Kai, Zhou, Shi‐Hao, Wang, Jian, Yin, Xu‐Guang, Gao, Xiao‐Fei, Liu, Zheng, Guo, Jun
• Format: Article
• Language: English
• Subjects: Antigens; Cancer; Cancer Vaccines - chemistry; Cancer Vaccines - immunology; Chemistry; fully synthetic vaccines; Humans; IgG antibody; Immunodominant Epitopes - immunology; Immunology; Lipids; Lipids - immunology; Liposomes; MCF-7 Cells; MUC1 antigen; Mucin-1 - immunology; NKT cells; Surface-Active Agents; Vaccines; αGalCer
• ISSN: 1861-4728; 1861-471X
• DOI: 10.1002/asia.201900448

The tumor‐associated antigen mucin 1 (MUC1) has been pursued as an attractive target for cancer immunotherapy, but the poor immunogenicity of the endogenous antigen hinders the development of vaccines capable of inducing effective anti‐MUC1 immunodominant responses. Herein, we prepared synthetic anti‐MUC1 vaccines in which the hydrophilic MUC1 antigen was N‐terminally conjugated to one or two palmitoyl lipid chains (to form amphiphilic Pam‐MUC1 or Pam2‐MUC1). These amphiphilic lipid‐tailed MUC1 antigens were self‐assembled into liposomes containing the NKT cell agonist αGalCer as an adjuvant. The lipid‐conjugated antigens reshaped the physical and morphological properties of liposomal vaccines. Promising results showed that the anti‐MUC1 IgG antibody titers induced by the Pam2‐MUC1 vaccine were more than 30‐ and 190‐fold higher than those induced by the Pam‐MUC1 vaccine and the MUC1 vaccine without lipid tails, respectively. Similarly, vaccines with the TLR1/2 agonist Pam3CSK4 as an adjuvant also induced conjugated lipid‐dependent immunological responses. Moreover, vaccines with the αGalCer adjuvant induced significantly higher titers of IgG antibodies than vaccines with the Pam3CSK4 adjuvant. Therefore, the non‐covalent assembly of the amphiphilic lipo‐MUC1 antigen and the NKT cell agonist αGalCer as a glycolipid adjuvant represent a synthetically simple but immunologically effective approach for the development of anti‐MUC1 cancer vaccines. Fully synthetic anti‐MUC1 vaccine candidates were prepared as liposomal formulations consisting of a MUC1 glycopeptide antigen and a lipid adjuvant. Promising results demonstrated that simple modification of the hydrophilic MUC1 antigen to generate amphiphilic lipoconjugates with dipalmitoyl chains impacts the biophysical properties of liposomes and significantly promotes the vaccine's immune responses.