Formalin-fixed tumor cells effectively induce antitumor immunity both in prophylactic and therapeutic conditions
Formalin-fixed tumor cells effectively induce antitumor immunity both in prophylactic and therapeutic conditions
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DOI：
10.1016/j.jdermsci.2004.02.003
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发表时间：
2004-05-01
影响因子：
4.6
通讯作者：
Himeno, K
中科院分区：
文献类型：
--
作者：
Obata, C;Zhang, MX;Himeno, K
背景：基于自体全肿瘤细胞的疫苗接种似乎是理想的，因为与使用单一确定抗原的疫苗接种相比，此类疫苗有可能引发针对肿瘤相关抗原的广泛类型的 T 细胞免疫反应。目的：我们修饰了甲醛（福尔马林）固定的小鼠黑色素瘤细胞，并研究了这些细胞作为免疫治疗肿瘤抗原来源的效用。方法：C5713L/6 或蛋白酶体激活剂 PA28α 敲除小鼠在肿瘤攻击之前或之后皮内接种 1% 福尔马林固定的 B16 细胞，每周 3 次。同时，利用基因枪技术将白细胞介素12基因转移到免疫部位周围的皮肤中。通过肿瘤生长、脾淋巴细胞中抗原特异性干扰素-γ的产生以及树突状细胞的激活来评估效果。结果：固定细胞直接诱导树突状细胞产生肿瘤坏死因子-α，比冷冻和解冻细胞更有效。超过 60% 的用固定细胞和白细胞介素 12 免疫的小鼠排斥了受攻击的 B16 肿瘤。这些小鼠的 CD4(+) T 细胞响应黑色素瘤细胞产生大量干扰素-γ。此外，这种联合治疗在治疗实验中显示出由CD8(+)和CD4(+)T细胞引发的抗肿瘤免疫。 PA28α/β似乎不是CD8+T细胞发育所必需的，尽管已知PA28α/β对于酪氨酸酶相关蛋白2（黑色素细胞谱系分化抗原之一）特异性的CD8+T细胞的发育是必需的。结论：这些结果表明福尔马林固定的自体黑色素瘤细胞有可能作为免疫治疗的有效抗原来源。 (C) 2004 年日本皮肤病研究学会。由爱思唯尔爱尔兰有限公司出版。保留所有权利。
Background: Autologous whole tumor cell-based vaccinations would seem to be ideal since such vaccinations, in contrast to vaccination with a single defined antigen, have the potential to elicit a broad type of T-cell immune response to tumor-associated antigens. Objective: We modified formaldehyde (formalin)-fixed mouse melanoma cells and investigated the utility of those cells as sources of tumor antigens for immunotherapy. Methods: C5713L/6 or the proteasome activator PA28alpha-knockout mice were intradermally inoculated with 1% formalin-fixed B16 cells three times at weekly intervals either before or after tumor challenge. Simultaneously, interleukin-12 gene was transferred into the skin around immunization sites using gene gun technology. The effects were evaluated by tumor growth, antigen-specific interferon-gamma production in splenic lymphocytes, and activation of dendritic cells. Results: Fixed cells directly induced production of tumor necrosis factor-alpha, in dendritic cells more effectively than did frozen and thawed cells. More than 60% of the mice immunized with fixed cells and interteukin-12 rejected the challenged B16 tumor. CD4(+) T cells from those mice produced a significant amount of interferon-gamma in response to melanoma cells. Furthermore, this combined treatment showed antitumor immunity initiated by CD8(+) and CD4(+) T cells in the therapeutic: experiments. PA28alpha/beta appeared not to be required for the development of CD8(+) T cells, although it is known to be essential for the development of CD8(+) T cells specific for tyrosinase-retated protein-2, one of melanocyte-lineage differentiated antigens. Conclusion: These results suggest that formalin-fixed autologous melanoma cells have a potential to function as effective antigen sources for immunotherapy. (C) 2004 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved.