MUC1 Vaccines, Comprised of Glycosylated or Non-Glycosylated Peptides or Tumor-Derived MUC1, Can Circumvent Immunoediting to Control Tumor Growth in MUC1 Transgenic Mice

Abstract

It remains challenging to produce decisive vaccines against MUC1, a tumor-associated antigen widely expressed by pancreas, breast and other tumors. Employing clinically relevant mouse models, we ruled out such causes as irreversible T-cell tolerance, inadequate avidity, and failure of T-cells to recognize aberrantly glycosylated tumor MUC1. Instead, every tested MUC1 preparation, even non-glycosylated synthetic 9mer peptides, induced interferon gamma-producing CD4+ and CD8+ T-cells that recognized glycosylated variants including tumor-associated MUC1. Vaccination with synthetic peptides conferred protection as long as vaccination was repeated post tumor challenge. Failure to revaccinate post challenge was associated with down-regulated tumor MUC1 and MHC molecules. Surprisingly, direct admixture of MUC1-expressing tumor with MUC1-hyperimmune T-cells could not prevent tumor outgrowth or MUC1 immunoediting, whereas ex vivo activation of the hyperimmune T-cells prior to tumor admixture rendered them curative. Therefore, surrogate T-cell preactivation outside the tumor bed, either in culture or by repetitive vaccination, can overcome tumor escape.

Tool for Rapid Analysis of Glycopeptide by Permethylation via One-Pot Site Mapping and Glycan Analysis

“…1–3 Unusual glycosylation has been deduced as the etiology behind various human pathological conditions such as hereditary disorders, 4,5 cardiovascular and liver disorders, 6–9 neurological diseases, 2 muscular dystrophies, 10 and different forms of cancer. 11,12 Both qualitative (aberrant glycan structures) and quantitative perturbations in the highly heterogeneous and complex glycans of both N-linked and/or O-linked glycoconjugate types have been associated with these abnormal conditions. 4,12 …”

“…11,12 Both qualitative (aberrant glycan structures) and quantitative perturbations in the highly heterogeneous and complex glycans of both N-linked and/or O-linked glycoconjugate types have been associated with these abnormal conditions. 4,12 …”

Restoring Anti-Oncodriver Th1 Responses with Dendritic Cell Vaccines in HER2/ neu -Positive Breast Cancer: Progress and Potential

“…More recently, MUC1 peptide vaccine study was able to induced INF gamma CD4 pos and CD8 pos T cells that recognized tumor-associated MUC1. Although only T-cell preactivation outside the tumor bed, either in culture or by repetitive vaccination, showed to overcome escape phase of tumor 'immunoediting' [72].…”

Anti‐MUC1 aptamer: A potential opportunity for cancer treatment

“…MUC1‐based treatments can be divided into three categories. The first is the use of MUC1 as a vaccine to induce an immune response against MUC1; for example, TG4010 is a recombinant vaccine encoding interleukin 2 and the MUC1 tumor‐associated antigen. This vaccine significantly improved the progression‐free survival in combination with chemotherapy, especially in patients with CD16‐, CD56‐, and CD69‐positive activated lymphocytes .…”