CpG motifs as proinflammatory factors render autochthonous tumors permissive for infiltration and destruction
CpG motifs as proinflammatory factors render autochthonous tumors permissive for infiltration and destruction
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DOI：
10.4049/jimmunol.172.10.5861
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发表时间：
2004-05-15
影响因子：
4.4
通讯作者：
Ganss, R
中科院分区：
文献类型：
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作者：
Garbi, N;Arnold, B;Ganss, R
在表达 SV40 T Ag (Tag) 作为新生肿瘤 Ag 的转基因小鼠模型中，免疫监视失败，胰岛细胞癌逐渐生长。为了开发一种有效根除实体生长肿瘤的抗癌策略，我们评估了具有富含胞嘧啶鸟嘌呤（CpG）基序（CpG-ODN）的免疫刺激性寡脱氧核苷酸（ODN）的有效性。在经典的疫苗接种方案中，Tag 与 CpG-ODN 作为佐剂一起施用。然而，尽管在体内成功激活了标签特异性 CTL 反应，但抗肿瘤疫苗接种仅在预防性环境下有效。组织学检查表明，一旦恶性环境建立，即使已启动的免疫细胞也无法浸润肿瘤。为了确保效应细胞不受限制，将高度激活的肿瘤 Ag 特异性 T 细胞转移到荷瘤小鼠体内。然而，这种治疗也未能导致肿瘤浸润和排斥。因此，我们进一步测试了 CpG-ODN 作为促炎剂与预激活标签特异性 CD4(+) 和 CD8(+) T 细胞转移相结合的功效。事实上，这种联合疗法p。事实证明它非常有效，因为 CpG-ODN 使胰岛素瘤能够进行大规模浸润和破坏。肿瘤组织的开口与组织驻留巨噬细胞对 CpG-ODN 的摄取以及血管内皮细胞上 ICAM 和 VCAM 等粘附分子的强烈上调相关。这些数据表明促炎试剂的全身应用极大地增强了效应细胞外渗到肿瘤组织中，这一观察结果对于临床环境中实体瘤的免疫治疗具有普遍重要意义。
In a transgenic mouse model expressing SV40 T Ag (Tag) as a de novo tumor Ag, immune surveillance fails and islet cell carcinomas grow progressively. To develop an anticancer strategy that would be effective in eradicating solid, autochthonously growing tumors, we evaluated the effectiveness of immunostimulatory oligodeoxynucleotides (ODN) with cytosine-guanine-rich (CpG) motifs (CpG-ODN). In a classical vaccination protocol, Tag was administered with CpG-ODN as adjuvant. The antitumor vaccination, however, was only effective in a prophylactic setting, despite the successful activation of a Tag-specific CTL response in vivo. Histological examination demonstrated that even primed immune cells failed to infiltrate tumors once a malignant environment was established. To ensure that effector cells were not limiting, highly activated tumor Ag-specific T cells were transferred into tumor-bearing mice. However, this treatment also failed to result in tumor infiltration and rejection. Therefore, we further tested the efficacy of CpG-ODN as a proinflammatory agent in combination with the transfer of preactivated Tag-specific CD4(+) and CD8(+) T cells. Indeed, this combination therapy p. roved to be highly effective, because CpG-ODN rendered insulinomas permissive for massive infiltration and destruction. The opening of tumor tissue correlated with uptake of CpG-ODN by tissue-resident macrophages and a strong up-regulation of adhesion molecules such as ICAM and VCAM on blood vessel endothelia. These data demonstrate that systemic application of proinflammatory reagents drastically enhances extravasation of effector cells into tumor tissue, an observation that is of general importance for immunotherapy of solid tumors in a clinical setting.