Gabrilovich D I, Nadaf S, Corak J, Berzofsky J A, Carbone D P
Simmons Cancer Center, UT Southwestern Medical Center, Dallas, Texas, USA.
Cell Immunol. 1996 May 25;170(1):111-9. doi: 10.1006/cimm.1996.0140.
Antitumor CTL responses were studied in a model tumor hearing 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-hearing 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.
在一个携带突变型人p53基因的模型肿瘤中研究了抗肿瘤CTL反应。我们发现在携带这些肿瘤的小鼠中，抗肿瘤CTL的诱导无效，这与这些动物树突状细胞（DC）功能的可测量缺陷有关。在本研究中，我们调查了成熟DC中这种缺陷的机制，发现功能性DC可以由携带肿瘤动物的骨髓生长产生。肿瘤细胞上清液不影响从荷瘤动物脾脏获得的成熟DC的功能，但在体外显著抑制了从对照小鼠骨髓产生功能性DC的能力。这表明肿瘤细胞可能释放阻断DC从前体细胞成熟早期阶段的因子。从荷瘤小鼠骨髓产生的DC显示出刺激同种异体T细胞、刺激抗突变p53肽特异性细胞毒性T细胞以及在对照小鼠体内诱导抗p53 CTL反应的正常潜力。用从对照小鼠骨髓产生的肽脉冲DC重复免疫（每4 - 5天一次）可阻断已建立肿瘤的进展。用从荷瘤小鼠脾脏获得的肽脉冲DC免疫小鼠（肿瘤注射后4周）不影响肿瘤生长，而用从荷瘤小鼠骨髓产生的肽脉冲DC免疫则导致显著延长生存期和延迟肿瘤生长。肿瘤进展与Th1/Th2细胞平衡向有利于Th2样细胞因子谱的方向变化有关，而有效的免疫与向Th1表型的转变有关。因此，用从荷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。
