Multiple Antigenic Peptides Based on H-2Kb–Restricted CTL Epitopes from Murine Heparanase Induce a Potent Antitumor Immune ResponseIn Vivo

Abstract

Accumulating research suggests that heparanase may be a universal tumor-associated antigen (TAA). Several heparanase T-cell epitopes from humans and mice have already been identified. However, because of low immunogenicity, polypeptide vaccines usually have difficulty inducing effective antitumor immune responses in vivo. In this study, to increase the immunogenicity of polypeptide vaccines, we designed and synthesized two four-branch multiple antigenic peptides (MAP) on the basis of mouse heparanase (mHpa) Tcell epitopes (mHpa398 and mHpa519). The dendritic cells (DC) from mice bone marrow loaded with above MAP vaccines from heparanase were used to evaluate immune response against various tumor cell lines, compared with immune response to their corresponding linear peptides, ex vivo and in vivo. We further assessed IFN-g release both in CD4 þ T-cell-depleted and nondepleted mice. The results showed that effectors generated from DCs, loaded with MAP-vaccinated mice splenocytes, induced a stronger immune response against target cells expressing both heparanase and H-2K b than did effectors generated from mice vaccinated with their corresponding linear peptides. Heparanase-specific CD8 þ T-cell responses induced by MAP and linear peptide vaccination required synergy of CD4 þ T cells. In addition, heparanse-derived MAP vaccines significantly inhibited the growth of B16 murine melanoma in C57BL/6 mice, while also increasing the survival rate of tumor-bearing mice. Our data suggest that MAP vaccines based on T-cell epitopes from heparanase are efficient immunogens for tumor immunotherapy.

hTERT-based therapy: A universal anticancer approach (Review)

“…It has not yet been determined whether these hTERT single epitope vaccines mediate an immunodominant response. This uncertainty may be due to their low molecular weight, rapid decline, weak immunogenicity, and their ineffective processing and presentation on cancer cells (37). To overcome the above problems, various carrier proteins and fusion proteins were used as vectors for delivering T-cell epitopes, while there is a risk that foreign proteins with high molecular weights will induce the immune response, rather than the target polypeptides.…”

“…hTERT peptides are processed and presented on the surface of DCs in the form of multiple-epitope that produce multiple CTL cell clones to induce an effective antitumor response using the MHC-I and -II pathways and avoid immune escape due to the loss of a single HLA allele. More attractively, the multiple antigenic peptide (MAP) system based on the core matrix lysine being coupled with four or eight strips of epitope monomer to form a branch-like structure, represents a unique way to generate anti-peptide antibodies (37). Theoretically, the MAP structure not only strengthens the specificity of the peptide chain structure and increases the molecular weight of the epitope peptides but also induces a high titer, high affinity antibody.…”

Double conjugation strategy to incorporate lipid adjuvants into multiantigenic vaccines

“…As a result, these peptides can elicit stronger in vivo immune responses than linear peptides. 17 We recently reported that modification of the 8Q min epitope from the E7 protein by replacing the C-terminal CCKCD sequence with SSKSD or SKKKK substantially diminished its immunogenicity. In contrast, deletion of the CCKCD sequence did not have any negative influence on the epitope potency.…”

A novel nanoparticle containing neuritin peptide with grp170 induces a CTL response to inhibit tumor growth

“…The cytotoxic T lymphocytes (CTLs) play a key role in immunity against tumors in vitro and in vivo [17][18][19]. CTLs can efficiently deliver tumor-associated antigens (TAAs) to the major histocompatibility complex (MHC) class I processing pathway of professional antigen-presenting cells (APCs), and especially dendritic cells (DCs) [20][21][22].…”