Dendritic cells in antitumor immune responses .2. Dendritic cells grown from bone marrow precursors, but not mature DC from tumor-bearing mice, are effective antigen carriers in the therapy of established tumors
Dendritic cells in antitumor immune responses .2. Dendritic cells grown from bone marrow precursors, but not mature DC from tumor-bearing mice, are effective antigen carriers in the therapy of established tumors
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DOI：
10.1006/cimm.1996.0140
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发表时间：
1996-05-25
影响因子：
4.3
通讯作者：
Carbone, DP
中科院分区：
文献类型：
--
作者：
Gabrilovich, DI;Nadaf, S;Carbone, DP
在一个携带人类p53突变基因的肿瘤模型中研究了抗肿瘤CTL反应。我们发现，在携带这些肿瘤的小鼠中，抗肿瘤CTL的无效诱导与来自这些动物的树突状细胞（DC）功能的可测量缺陷相关。在本研究中，我们研究了成熟DC中这种缺陷的机制，并发现功能性DC可以通过携带肿瘤动物的骨髓生长产生。肿瘤细胞上清液不影响荷瘤动物脾脏成熟DC的功能，但显著抑制对照小鼠骨髓在体外产生功能性DC的能力。这表明肿瘤细胞可能从前体释放出阻止早期DC成熟的因子。从荷瘤小鼠骨髓中产生的DC在对照小鼠体内表现出正常的刺激同种异体T细胞、刺激抗突变p53肽特异性细胞毒T细胞和诱导抗p53 CTL反应的潜能。用对照小鼠骨髓产生的肽脉冲DC重复免疫（每4-5天）可阻断已建立的肿瘤的进展。用荷瘤小鼠脾脏的肽脉冲DC免疫小鼠（肿瘤注射后4周）对肿瘤生长无影响，而用荷瘤小鼠骨髓的肽脉冲DC免疫小鼠可显著延长存活时间，延缓肿瘤生长。肿瘤进展与Th1/Th2细胞平衡的改变有关，有利于Th2样细胞因子谱，而有效免疫与Th1表型的转变有关。因此，用肿瘤宿主干细胞产生的突变型p53肽脉冲DC频繁免疫小鼠，可诱导与Th1细胞产生相关的有效抗肿瘤CTL反应，并导致显著的抗肿瘤作用。(C) 1996学术出版社，Inc.
Antitumor CTL responses were studied in a model tumor bearing a mutant human p53 gene. We found ineffective induction of antitumor CTL in mice bearing these tumors associated with measurable defects in the function of dendritic cells (DC) from these animals, In this study we investigate the mechanism of this defect in mature DC and find that functional DC can be generated by growth from the bone marrow of tumor-bearing animals. Tumor cell supernatants did not affect the function of mature DC obtained from the spleen of tumor-bearing animals, but significantly suppressed the ability to generate functional DC from the bone marrow of control mice in vitro. This suggests that tumor cells may release factors which block early stages of DC maturation from precursors. DC generated from the bone marrow of tumor-bearing mice showed normal potential to stimulate allogeneic T cells, to stimulate anti-mutant p53 peptide-specific cytotoxic T cells, and to induce anti-p53 CTL responses in vivo in control mice. Repeated immunization with peptide-pulsed DC generated from the bone marrow of control mice (every 4-5 days) blocked progression of established tumors. Immunization of mice with peptide-pulsed DC obtained from the spleen of tumor-bearing mice (4 weeks after tumor injection) did not affect the tumor growth, whereas immunization with peptide-pulsed DC generated from bone marrow of tumor-bearing mice resulted in significantly prolonged survival and delayed tumor growth. Tumor progression was associated with change of the balance Th1/Th2 cells in favor of the Th2-like cytokine profile, while effective immunization was associated with a shift to the Th1 phenotype. Thus, frequent immunization of mice with mutant p53 peptide-pulsed DC generated from stem cells of tumor-bearing hosts can induce effective antitumor CTL responses associated with production of Th1 cells and lead to significant antitumor effects. (C) 1996 Academic Press, Inc.