Ex vivo targeting of the macrophage mannose receptor generates anti-tumor CTL responses

MUC1 is highly expressed in adenocarcinomas and is a possible target for im munotherapy. In mice, oxidized mannan linked to MUC1 (M-FP), given in vivo, induces potent MHC-restricted CTL and tumor protection. Because of the res istance of cancer patients to immunization, ex vivo immunization of macroph age/dendritic cells was examined using oxidized mannan MUC1 to target the m annose receptor and the MHC Class I antigen presentation pathway. Here, we show that murine mannose receptor (MR) bearing macrophages derived from per itoneal exudate cells (PEC) and cultured ex vivo with M-FP can, after adopt ive transfer, efficiently present MUC1 to T cells, leading to the generatio n of high frequency of CTL and protection from tumor challenge. Mice immuni zed once with syngeneic PEC pulsed with M-FP elicit a similar CTLp frequenc y to that obtained with three in vivo immunizations. Targeting the MR is cr ucial to obtain high frequency CTL, and without oxidiation the CTLp frequen cy was low. GM-CSF is important, as GM-CSF o/o mice gave reduced responses, a deficiency corrected by in vivo GMCSF. In addition, the treatment of mac rophages ex vivo with GM-CSF gave enhanced responses and treating mice with GMCSF prior to M-FP immunizations also enhanced cellular responses. M-FP t argets the MR and ensures rapid passage of peptides to Class I molecules, a nd can also directly stimulate in vitro IL-12 production by macrophages. Wh ile many studies are now focussing on dendritic cells, in this study the ce lls involved were adherent F4/80(+) 33D1(-) macrophages. The findings could be of benefit for the immunization of patients with cancer. (C) 2000 Elsev ier Science Ltd. All rights reserved.