Vaccination with metastasis-related tumor associated antigen TPD52 and CpG/ODN induces protective tumor immunity

Abstract

Tumor protein D52 (TPD52) is involved in transformation and metastasis and has been shown to be over-expressed in tumor cells compared to normal cells and tissues. Murine TPD52 (mD52) shares 86% protein identity with the human TPD52 orthologue (hD52). To study TPD52 protein as a target for active vaccination recombinant, mD52 was administered as a protein-based vaccine. Naïve mice were immunized with either mD52 protein and CpG/ODN as a molecular adjuvant or CpG/ODN alone. Two weeks following the final immunization, mice were challenged s.c. with syngeneic tumor cells that over-express mD52. Two distinct murine tumor cell lines were used for challenge in this model, mKSA and 3T3.mD52. Half of the mice immunized with mD52 and CpG/ODN rejected or delayed onset of mKSA s.c. tumor cell growth, and 40% of mice challenged with 3T3.mD52 rejected s.c. tumor growth, as well as the formation of spontaneous lethal lung metastases. Mice immunized with mD52 and CpG/ODN generated detectable mD52-specific IgG antibody responses indicating that mD52 protein vaccination induced an adaptive immune response. In addition, mice that rejected tumor challenge generated tumor-specific cytotoxic T lymphocytes' responses. Importantly, microscopic and gross evaluation of organs from mD52 immunized mice revealed no evidence of autoimmunity as assessed by absence of T cell infiltration and absence of microscopic pathology. Together, these data demonstrate that mD52 vaccination induces an immune response that is capable of rejecting tumors that over-express mD52 without the induction of harmful autoimmunity.

Proteomic Profiling of Triple-negative Breast Carcinomas in Combination With a Three-tier Orthogonal Technology Approach Identifies Mage-A4 as Potential Therapeutic Target in Estrogen Receptor Negative Breast Cancer

“…S1), a protein frequently overexpressed in breast and other cancers (31) and a potential tumor antigen target for immunotherapy (32)(33)(34), D-3-phosphoglycerate dehydrogenase (PHGDH) (IEF SSP#2512; NEPHGE SSP# 2601, Supplemental Figs. S1 and S2, respectively), a protein involved in the serine biosynthetic pathway that was recently identified in ER-negative breast cancer (35,36), and melanoma-associated antigen 4 (Mage-A4) (Fig.…”

Overexpressed oncogenic tumor-self antigens

“…99 When mD52 DNA vaccination was compared head-to-head with hD52 DNA vaccination, the partial xeno-antigen (hD52) was more effective at protecting against tumor challenge, however both strategies induced durable responses that rejected secondary tumor challenge months later. 100 The T cell cytokine secretion patterns for all the TPD52 vaccine studies demonstrated that a T H -1-type cellular immune response was responsible for tumor rejection [97][98][99] and that a complete response may be hindered by a potentially unique subset of CD8C IL-10C regulatory T cells. 100 An overlapping peptide-based mD52 vaccine, evaluated independently, demonstrated efficacy in a murine breast cancer model.…”

“…First, the successful use of the basic vaccine formulation demonstrated that a tumor self-protein can be immunogenic when delivered as a simple protein, peptides or plasmid DNA. Second, TPD52 vaccines prevent tumor formation without inducing autoimmunity, 97 even when classical CD4C CD25C Treg cells were depleted. 98,100 These studies suggest that TPD52-specific T cells are present and not completely eliminated by central tolerance, and that peripheral tolerance is involved in obstructing complete tumor rejection to include suppression by an as yet undefined but potentially unique subset of CD8C Treg cells.…”

“…mD52 protein administered without CpG-ODN failed to elicit an immune response, indicating that the TLR agonist was necessary to break tolerance. 97 Subcutaneous injection of mD52 protein with CpG-ODN required concomitant CD4CCD25C T regulatory (Treg) cell depletion to improve tumor protection. 98 DNAbased vaccine approaches using the TRAMP model of prostate cancer demonstrated that mD52 DNA vaccination induced an immune response that prevented tumors with increased efficacy when administered with GM-CSF and induced long-term immunologic memory.…”

TPD52: A Novel Vaccine Target for Prostate Cancer

“…Thus, D52 represents a non-mutated over-expressed self-oncoantigen. We demonstrated for the first time that mD52 induces protection against tumor challenge when administered as recombinant protein-based vaccine with CpG-ODN [13]. We also reported that mD52 DNA vaccination induced an immune response that rejected tumors in the transgenic adenocarcinoma of the mouse prostate (TRAMP) model of prostate cancer.…”