Abstract
Mucin 1 (MUC1), a well-known tumor-associated antigen and attractive target for tumor immunotherapy, is overexpressed in most human epithelial adenomas with aberrant glycosylation. However, its low immunogenicity impedes the development of MUC1-targeted antitumor vaccines. In this study, we investigated three liposomal adjuvant systems containing toll-like receptor 4 (TLR4) agonist monophosphoryl lipid A (MPLA) and auxiliary lipids of different charges: cationic lipid dimethyldioctadecylammonium (DDA), neutral lipid distearoylglycerophosphocholine (DSPC) or anionic lipid dioleoylphosphatidylglycerol (DOPG), respectively. ELISA assay evidenced that the positively charged DDA/MPLA liposomes are potent immune activators, which induced remarkable levels of anti-MUC1 antibodies and exhibited robust Th1-biased immune responses. Importantly, the antibodies induced by DDA/MPLA liposomes efficiently recognized and killed MUC1-positive tumor cells through complement-mediated cytotoxicity. In addition, antibody titers in mice immunized with P2-MUC1 vaccine were significantly higher than those from mice immunized with P1-MUC1 or MUC1 vaccine, which indicated that the lipid conjugated on MUC1 antigen also played important role for immunomodulation. This study suggested that the liposomal DDA/MPLA with lipid-MUC1 is a promising antitumor vaccine, which can be used for the immunotherapy of various epithelial carcinomas represented by breast cancer.
Highlights
Mucin1 (MUC1), a transmembrane glycoprotein highly overexpressed and aberrantly glycosylated on many tumor tissues including ovarian, breast, pancreatic, prostate and ovarian carcinomas (Hollingsworth and Swanson, 2004; Kufe, 2009; Nath and Mukherjee, 2014; Chen et al, 2021)
Monophosphoryl lipid A (MPLA), a toll-like receptor 4 (TLR4) agonist optimized from Salmonella minnesota lipopolysaccharide (LPS), is a promising immunostimulant licensed for use in human vaccines preventing viral infections (Alderson et al, 2006; Vacchelli et al, 2012; Gao and Guo, 2018; SCHEME 1 | Synthesis of Mucin 1 (MUC1) glycopeptide and lipoglycopeptides by solid phase peptide synthesis (SPPS)
The resin-bound peptide MUC1 with Tn glycosylation on the PDTRP motif was synthesized via the solid phase methodology using Fmoc strategy (Scheme 1 and Supplementary Schemes S1–S4)
Summary
Mucin (MUC1), a transmembrane glycoprotein highly overexpressed and aberrantly glycosylated on many tumor tissues including ovarian, breast, pancreatic, prostate and ovarian carcinomas (Hollingsworth and Swanson, 2004; Kufe, 2009; Nath and Mukherjee, 2014; Chen et al, 2021). Liposomal Cancer Vaccine Containing DDA/MPLA glycoprotein has been considered as one of the favorable targets for the development of cancer immunotherapy (Barratt-Boyes, 1996; Singh and Bandyopadhyay, 2007; Pillai et al, 2015; Dhanisha et al, 2018; Brockhausen and Melamed, 2021). Monophosphoryl lipid A (MPLA), a TLR4 agonist optimized from Salmonella minnesota lipopolysaccharide (LPS), is a promising immunostimulant licensed for use in human vaccines preventing viral infections (Alderson et al, 2006; Vacchelli et al, 2012; Gao and Guo, 2018; SCHEME 1 | Synthesis of MUC1 glycopeptide and lipoglycopeptides by solid phase peptide synthesis (SPPS)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
