Ex vivo targeting of the macrophage mannose receptor generates anti-tumor CTL responses
Ex vivo targeting of the macrophage mannose receptor generates anti-tumor CTL responses
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DOI：
10.1016/s0264-410x(00)00090-6
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发表时间：
2000-07-15
期刊：
影响因子：
5.5
通讯作者：
McKenzie, IFC
中科院分区：
文献类型：
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作者：
Apostolopoulos, V;Barnes, N;McKenzie, IFC
MUC 1在腺癌中高度表达，是免疫治疗的可能靶点。在小鼠中，与MUC 1连接的氧化甘露聚糖（M-FP），在体内给药，诱导有效的MHC限制性CTL和肿瘤保护。由于癌症患者对免疫的抗性，使用氧化的甘露聚糖MUC 1靶向甘露糖受体和MHC I类抗原呈递途径来检查巨噬细胞/树突细胞的离体免疫。在这里，我们表明，小鼠甘露糖受体（MR）轴承巨噬细胞来源于腹膜渗出细胞（PEC）和培养离体与M-FP，过继转移后，可以有效地提出MUC 1的T细胞，导致产生高频率的CTL和保护肿瘤的挑战。用M-FP脉冲的同基因PEC免疫一次的小鼠引起的CTLp频率与三次体内免疫获得的频率相似。靶向MR是获得高频率CTL的关键，并且在没有氧化的情况下，CTLp频率低。GM-CSF是重要的，因为GM-CSF o/o小鼠的反应降低，这是一种通过体内GMCSF校正的缺陷。此外，用GM-CSF离体处理巨噬细胞产生增强的应答，并且在M-FP免疫之前用GMCSF处理小鼠也增强了细胞应答。M-FP靶向MR并确保肽快速通过I类分子，并且还可以直接刺激巨噬细胞的体外IL-12产生。虽然现在许多研究都集中在树突状细胞上，但在本研究中，涉及的细胞是粘附的F4/80（+）33 D1（-）巨噬细胞。这一发现可能对癌症患者的免疫接种有益。(C)2000爱思唯尔科技有限公司版权所有。
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 oxidiation the CTLp frequency 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 macrophages ex vivo with GM-CSF gave enhanced responses and treating mice with GMCSF 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. (C) 2000 Elsevier Science Ltd. All rights reserved.