Efficient Eradication of Subcutaneous but Not of Autochthonous Gastric Tumors by Adoptive T Cell Transfer in an SV40 T Antigen Mouse Model
Efficient Eradication of Subcutaneous but Not of Autochthonous Gastric Tumors by Adoptive T Cell Transfer in an SV40 T Antigen Mouse Model
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DOI：
10.4049/jimmunol.0903231
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发表时间：
2010-08-15
影响因子：
4.4
通讯作者：
Endres, Stefan
中科院分区：
文献类型：
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作者：
Bourquin, Carole;von der Borch, Philip;Endres, Stefan
在胃癌中，需要新的治疗策略，特别是对于不可切除的肿瘤和微转移的治疗。我们研究了免疫治疗在胃癌本地模型（CEA424-SV40 T Ag (TAg) 转基因小鼠）中的疗效。对本土肿瘤和皮下肿瘤的治疗效果评估了衍生细胞系 mGC3 诱导的肿瘤。在野生型小鼠中，负载受辐射肿瘤细胞和 CpG 寡核苷酸的树突状细胞疫苗诱导了针对 mGC3 的有效细胞毒性 T 细胞和记忆反应。肿瘤。相比之下，s.c. 都没有。 CEA424-SV40 TAg 小鼠中的本土肿瘤对疫苗接种也没有反应，表明对 SV40 TAg 的耐受性。为了检查这些小鼠的肿瘤是否主要可用于免疫治疗，将免疫野生型小鼠的脾细胞过继转移至 CEA424-SV40 TAg 转基因小鼠中。接受治疗的小鼠皮下组织完全消退。与肿瘤内 CD8 和 CD4 T 细胞浸润相关的肿瘤。相比之下，同一只小鼠的原位胃肿瘤浸润不良且没有消退。因此，即使存在活跃的抗肿瘤 T 细胞反应，本地胃肿瘤也不会对免疫治疗产生反应。这是首次比较皮下移植和过继性 T 细胞转移的效果。同一动物体内的肿瘤和本土肿瘤。我们的结果表明，在胃癌患者中，如果没有针对肿瘤微环境的额外治疗策略，即使是强烈的抗肿瘤 T 细胞反应也无法有效穿透肿瘤。免疫学杂志，2010，185：2580-2588。
In stomach cancer, there is a need for new therapeutic strategies, in particular for the treatment of unresectable tumors and micrometastases. We investigated the efficacy of immunotherapy in an autochthonous model of gastric cancer, the CEA424-SV40 T Ag (TAg) transgenic mice. Treatment efficacy against both the autochthonous tumors and s.c. tumors induced by the derived cell line mGC3 were assessed. In wild-type mice, a dendritic cell vaccine loaded with irradiated tumor cells combined with CpG oligonucleotides induced efficient cytotoxic T cell and memory responses against mGC3 s.c. tumors. In contrast, neither s.c. nor autochthonous tumors responded to vaccination in CEA424-SV40 TAg mice, indicating tolerance to the SV40 TAg. To examine whether tumors in these mice were principally accessible to immunotherapy, splenocytes from immune wild-type mice were adoptively transferred into CEA424-SV40 TAg transgenic mice. Treated mice showed complete regression of the s.c. tumors associated with intratumoral infiltrates of CD8 and CD4 T cells. In contrast, the autochthonous gastric tumors in the same mice were poorly infiltrated and did not regress. Thus, even in the presence of an active anti-tumoral T cell response, autochthonous gastric tumors do not respond to immunotherapy. This is the first comparison of the efficacy of adoptive T cell transfer between transplanted s.c. tumors and autochthonous tumors in the same animals. Our results suggest that in gastric cancer patients, even a strong anti-tumor T cell response will not efficiently penetrate the tumor in the absence of additional therapeutic strategies targeting the tumor micro-environment. The Journal of Immunology, 2010, 185: 2580-2588.