Local administration of dendritic cells inhibits established breast tumor growth: implications for apoptosis-inducing agents.
Local administration of dendritic cells inhibits established breast tumor growth: implications for apoptosis-inducing agents.
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发表时间：
2001
期刊：
影响因子：
11.2
通讯作者：
Kimberly A. Candido;Koichi Shimizu;Julie C. McLaughlin;Robin G. Kunkel;Jennifer A. Fuller;Bruce G. Redman;Elaine K. Thomas;Brian J. Nickoloff;James J. Mulé
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作者：
Kimberly A. Candido;Koichi Shimizu;Julie C. McLaughlin;Robin G. Kunkel;Jennifer A. Fuller;Bruce G. Redman;Elaine K. Thomas;Brian J. Nickoloff;James J. Mulé
树突状细胞 (DC) 可以有效地从凋亡细胞中获取外源抗原，并诱导 MHC I 类限制性抗原特异性 CTL。 DCs在实体瘤块内的原位积累与更良好的预后间接相关。因此，树突状细胞可能提供一种有效的方法来触发肿瘤内的免疫反应，特别是在那些含有显着细胞凋亡的肿块中。我们检查了 DC 的递送是否可以单独影响具有相对较高凋亡指数的肿瘤的进行性生长。我们在皮下组织中检测到显着的早期细胞凋亡。正在生长的小鼠 MT-901 乳腺癌。 DCs在体外可以有效吞噬MT-901肿瘤凋亡细胞。瘤内注射同基因而非同种异体 DC 可显着抑制 MT-901 肿瘤生长。肿瘤的组织学检查显示在 DC 注射期间和之后有强烈的单核细胞浸润。肿瘤生长抑制相对放射敏感并且依赖于宿主来源的CD8+T细胞。给予肿瘤坏死因子α可显着提高肿瘤细胞凋亡的基线水平，从而产生更大的DC介导的抗肿瘤作用。在瘤内递送之前，首先用外源辅助蛋白匙孔血蓝蛋白脉冲 DC，并将其与白细胞介素 2 的全身给药相结合，也可以增强抗肿瘤效果。来自治疗动物的脾细胞显示出更高水平的特异性 CTL 活性和细胞因子的产生。原位肿瘤细胞凋亡的水平似乎在 DC 介导的抗肿瘤作用中发挥着关键作用。讨论了这些发现对基于 DC 的肿瘤治疗策略的潜在影响。
Dendritic cells (DCs) can efficiently acquire foreign antigen(s) from apoptotic cells and induce MHC class I-restricted, antigen-specific CTLs. An accumulation of DCs within solid tumor masses in situ has been associated indirectly with a more favorable prognosis. Therefore, DCs may offer an efficient means for triggering immune responses within tumors, particularly in those masses containing significant apoptosis. We examined whether delivery of DCs could, alone, impact on the progressive growth of a tumor with a relatively high apoptotic index. We detected significant early apoptosis within the mass of a s.c. growing murine MT-901 breast carcinoma. DCs could efficiently engulf MT-901 tumor apoptotic cells in vitro. Intratumoral injections of syngeneic but not allogeneic DCs resulted in significant inhibition of MT-901 tumor growth. Histological examination of the tumor revealed intense mononuclear cell infiltration during and after DC injections. Tumor growth inhibition was relatively radiosensitive and dependent on host-derived CD8+ T cells. The baseline level of tumor apoptosis could be increased substantially by tumor necrosis factor alpha administration, leading to a greater DC-mediated antitumor effect. The antitumor effect could also be enhanced by first pulsing DCs with the foreign helper protein, keyhole limpet hemocyanin, prior to intratumoral delivery and combining it with the systemic administration of interleukin 2. Splenocytes from treated animals showed heightened levels of specific CTL activity and production of cytokines. The level of in situ tumor apoptosis appears to play a critical role in DC-mediated antitumor effects. The potential implication of these findings in DC-based tumor therapy strategies is discussed.