title: Ex vivo targeting of the macrophage mannose receptor generates anti-tumor CTL responses.
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.
authors.affiliation: The Austin Research Institute, Studley Rd, 3084, Vic., Heidelberg, Australia. v.apostolopoulos@ari.unimelb.edu.au
authors.forename: V
authors.initials: V
authors.lastname: Apostolopoulos
authors.forename: N
authors.initials: N
authors.lastname: Barnes
authors.forename: G A
authors.initials: GA
authors.lastname: Pietersz
authors.forename: I F
authors.initials: IF
authors.lastname: McKenzie
mesh_terms: D000818:Animals; D000921:Antibody-Producing Cells / Q000502:physiology; D003713:Dendritic Cells / Q000502:physiology; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D006801:Humans; D018664:Interleukin-12 / Q000235:genetics; D037181:Lectins, C-Type; D008264:Macrophages / Q000502:physiology*; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D018396:Mucin-1 / Q000276:immunology* / Q000494:pharmacology; D009369:Neoplasms / Q000276:immunology*; D010084:Oxidation-Reduction; D051381:Rats; D011956:Receptors, Cell Surface / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
chemical_list: D037181:Lectins, C-Type; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins; D018396:Mucin-1; D011956:Receptors, Cell Surface; D014409:Tumor Necrosis Factor-alpha; D018664:Interleukin-12; D016178:Granulocyte-Macrophage Colony-Stimulating Factor