Ex Vivo Targeting of the Macrophage Mannose Receptor Generates Anti-Tumor CTL Responses

Vaccine. 2000 Jul 15;18(27):3174-84. doi: 10.1016/s0264-410x(00)00090-6.

Abstract

MUC1 is highly expressed in adenocarcinomas and is a possible target for immunotherapy. In mice, oxidized mannan linked to MUC1 (M-FP), given in vivo, induces potent MHC-restricted CTL and tumor protection. Because of the resistance of cancer patients to immunization, ex vivo immunization of macrophage/dendritic cells was examined using oxidized mannan MUC1 to target the mannose receptor and the MHC Class I antigen presentation pathway. Here, we show that murine mannose receptor (MR) bearing macrophages derived from peritoneal exudate cells (PEC) and cultured ex vivo with M-FP can, after adoptive transfer, efficiently present MUC1 to T cells, leading to the generation of high frequency of CTL and protection from tumor challenge. Mice immunized once with syngeneic PEC pulsed with M-FP elicit a similar CTLp frequency to that obtained with three in vivo immunizations. Targeting the MR is crucial to obtain high frequency CTL, and without oxidation the CTLp frequency was low. GM-CSF is important, as GM-CSF o/o mice gave reduced responses, a deficiency corrected by in vivo GM-CSF. In addition, the treatment of macrophages ex vivo with GM-CSF gave enhanced responses and treating mice with GM-CSF prior to M-FP immunizations also enhanced cellular responses. M-FP targets the MR and ensures rapid passage of peptides to Class I molecules, and can also directly stimulate in vitro IL-12 production by macrophages. While many studies are now focussing on dendritic cells, in this study the cells involved were adherent F4/80+ 33D1- macrophages. The findings could be of benefit for the immunization of patients with cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibody-Producing Cells / physiology
  • Dendritic Cells / physiology
  • Granulocyte-Macrophage Colony-Stimulating Factor / pharmacology
  • Humans
  • Interleukin-12 / genetics
  • Lectins, C-Type*
  • Macrophages / physiology*
  • Mannose-Binding Lectins*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred DBA
  • Mucin-1 / immunology*
  • Mucin-1 / pharmacology
  • Neoplasms / immunology*
  • Oxidation-Reduction
  • Rats
  • Receptors, Cell Surface / immunology*
  • T-Lymphocytes, Cytotoxic / immunology*
  • Tumor Necrosis Factor-alpha / genetics

Substances

  • Lectins, C-Type
  • Mannose-Binding Lectins
  • Mucin-1
  • Receptors, Cell Surface
  • Tumor Necrosis Factor-alpha
  • mannose receptor
  • Interleukin-12
  • Granulocyte-Macrophage Colony-Stimulating Factor