Abstract
Mucin 4 (MUC4) is a high molecular weight glycoprotein that is differentially overexpressed in pancreatic cancer (PC), functionally contributes to disease progression, and correlates with poor survival. Further, due to its aberrant glycosylation and extensive splicing, MUC4 is a potential target for cancer immunotherapy. Our previous studies have demonstrated the utility of amphiphilic polyanhydride nanoparticles as a useful platform for the development of protein-based prophylactic and therapeutic vaccines. In the present study, we encapsulated purified recombinant human MUC4-beta (MUC4β) protein in polyanhydride (20:80 CPTEG:CPH) nanoparticles (MUC4β-nanovaccine) and evaluated its ability to activate dendritic cells and induce adaptive immunity. Immature dendritic cells when pulsed with MUC4β-nanovaccine exhibited significant increase in the surface expressions of MHC I and MHC II and costimulatory molecules (CD80 and CD86), as well as, secretion of pro-inflammatory cytokines (IFN-γ, IL-6, and IL-12) as compared to cells exposed to MUC4β alone or MUC4β mixed with blank nanoparticles (MUC4β+NP). Following immunization, as compared to the other formulations, MUC4β-nanovaccine elicited higher IgG2b to IgG1 ratio of anti-MUC4β-antibodies suggesting a predominantly Th1-like class switching. Thus, our findings demonstrate MUC4β-nanovaccine as a novel platform for PC immunotherapy.
Highlights
Pancreatic cancer (PC) has a dismal prognosis with an overall survival rate of 8%, due to the limited efficacy of existing treatment modalities including surgery, chemotherapy, and radiation [1, 2]
The 20:80 CPTEG:CPH NPs loaded with 3% wt/wt MUC4β were synthesized via solid-oil-oil double emulsion
As compared to sera from the mice immunized with MUC4β+Freund’s adjuvant (FA), we observed a significant increase of IL-12/ IL-23p40 (~2.2-folds) and IFN-γ (~4.5-folds) cytokines in the sera of MUC4β-nanovaccine-immunized mice (Figure 5B, 5C)
Summary
Pancreatic cancer (PC) has a dismal prognosis with an overall survival rate of 8%, due to the limited efficacy of existing treatment modalities including surgery, chemotherapy, and radiation [1, 2]. It was shown that the mice immunized with MUC4 glycopeptides conjugated to tetanus toxoid induced strong immune responses and predominantly produced IgG1 antibodies [20] Such “cherry-picked” immunodominant peptides limit the epitopes that can be employed to elicit immune responses in an unbiased manner, and are of limited translational value. While the large size of MUC4 can potentially provide a large epitope repertoire for eliciting potent immune responses, the production and purification of intact megadalton MUC4 protein is challenging. To circumvent these problems, this study investigated the utility of recombinant MUC4β subunit for tumor vaccine development
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