A cancer vaccine based on fluorine-modified sialyl-Tn induces robust immune responses in a murine model

Oncotarget. 2017 Jul 18;8(29):47330-47343. doi: 10.18632/oncotarget.17646.

Abstract

Development of an effective vaccine to target tumor associated carbohydrate antigens, aberrantly expressed on the cell surface of various carcinomas, is an appealing approach toward cancer immunotherapy. However, a major problem of carbohydrate antigens is their poor immunogenicity. Immunization with modified-carbohydrate antigens could improve the immunogenicity and induce cross reaction with the native carbohydrate antigens. In this study, we investigated the antitumor ability of three fluoro-substituted sialyl-Tn (STn) analogues (2, 3, 4) coupled to KLH (keyhole limpet hemocyanin) and studied the mechanism of tumor immunotherapy of the vaccines in a murine model of colon cancer. Vaccination with 4-KLH, in which the two N-acetyl groups of STn are substituted with N-fluoroacetyl groups, could remarkably prolong the survival of tumor-bearing mouse and resulted in a significant reduction in tumor burden of lungs compared with STn-KLH (1-KLH). The vaccine 4-KLH could provoke stronger cytotoxic T lymphocytes immune response, T helper (Th) cell-mediated immune response and an earlier-stage Th1 immune response than 1-KLH, thus breaking immune tolerance and generating a therapeutic response. The 4-KLH vaccine induced strong tumor-specific anti-STn antibodies which could mediate complement-dependent cytotoxicity and antibody-dependent cell-mediated cytotoxicity against human tumor cells. Moreover, in the absence of adjuvant, 4-KLH still elicited stronger immune responses than 1-KLH. Our data suggested that 4-KLH is superior in tumor prevention. The strategic hapten fluorination may be a potential approach applicable to the vaccines development for the cancer immunotherapy.

Keywords: cancer immunotherapy; cross reaction; fluoro-substituted STn; glycoconjugate vaccine; tumor-associated carbohydrate antigen.

MeSH terms

  • Adjuvants, Immunologic
  • Animals
  • Antibody Formation / immunology
  • Antibody-Dependent Cell Cytotoxicity
  • Antigens, Tumor-Associated, Carbohydrate / immunology
  • Cancer Vaccines / administration & dosage
  • Cancer Vaccines / chemistry
  • Cancer Vaccines / immunology*
  • Cell Line, Tumor
  • Cytotoxicity, Immunologic
  • Disease Models, Animal
  • Female
  • Fluorine* / chemistry
  • Immunity*
  • Immunity, Cellular
  • Immunization
  • Immunotherapy
  • Mice
  • Neoplasms / immunology*
  • Neoplasms / mortality
  • Neoplasms / pathology*
  • Neoplasms / therapy
  • T-Lymphocyte Subsets / immunology
  • T-Lymphocyte Subsets / metabolism

Substances

  • Adjuvants, Immunologic
  • Antigens, Tumor-Associated, Carbohydrate
  • Cancer Vaccines
  • sialosyl-Tn antigen
  • sialyl-Tn antigen-keyhole-limpet hemocyanin conjugate
  • Fluorine