Local Administration of GITR Agonistic Antibody Induces a Stronger Antitumor Immunity than Systemic Delivery
Local Administration of GITR Agonistic Antibody Induces a Stronger Antitumor Immunity than Systemic Delivery
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GITR 激动性抗体的局部给药可诱导比全身给药更强的抗肿瘤免疫
DOI：
10.1038/s41598-019-41724-x
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发表时间：
2019
影响因子：
4.6
通讯作者：
Aoki Kazunori
中科院分区：
文献类型：
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作者：
Narumi Kenta;Miyakawa Reina;Shibasaki Chihiro;Henmi Marina;Mizoguchi Yukihiro;Ueda Ryosuke;Hashimoto Hisayoshi;Hiraoka Nobuyoshi;Yoshida Teruhiko;Aoki Kazunori
抗糖皮质激素诱导的TNF受体（GITR）激动抗体（Ab）通过刺激效应T细胞和抑制调节性T细胞活性诱导抗肿瘤免疫。为了增强GITR抗体介导的肿瘤免疫，我们重点研究了肿瘤内途径，因为肿瘤局部高浓度的抗体只会激活肿瘤浸润的T细胞。首先，在小鼠结肠癌模型中，我们发现瘤内递送Ab显著增加了效应T细胞浸润肿瘤的数量，并且比腹腔和静脉注射更有效地抑制肿瘤生长。然后，我们发现将Ab注射到肿瘤周围区域诱导了与肿瘤内注射相似水平的全身抗肿瘤免疫。因此，我们假设局部给药的Ab转移到肿瘤引流淋巴结（tdln）在诱导有效免疫中起重要作用。事实上，在tdln中检测到瘤内或瘤周注射的Ab，并且切除注射了Ab的tdln可显著降低GITR抗体介导的全身肿瘤免疫。肿瘤内注射显示脾脏中的自身反应性T细胞数量少于腹腔注射。与全身递送相比，肿瘤内递送GITR抗体是一种很有希望诱导有效免疫的方法。
An anti-glucocorticoid induced TNF receptor (GITR) agonistic antibody (Ab) induces an antitumor immunity with both stimulation of effector T cells and inhibition of regulatory T cell activity. To enhance GITR Ab-mediated tumor immunity, we focused on the intratumoral route, since a tumor-localized high concentration of Ab would confer activation of only tumor-infiltrating T cells. First, in a murine colon cancer model, we showed that the intratumoral delivery of Ab significantly increased the number of effector T cells infiltrated into tumors, and suppressed tumor growth more effectively than the intraperitoneal and intravenous injections did. Then, we found that the injection of Ab into the peritumoral area induced a systemic antitumor immunity at a similar level to the intratumoral injection. Therefore, we hypothesized that the transfer of locally administrated Ab into tumor-draining lymph nodes (TDLNs) plays an important role in inducing an effective immunity. In fact, intratumorally or peritumorally injected Ab was detected in TDLNs, and resection of Ab-injected TDLNs significantly reduced GITR Ab-mediated systemic tumor immunity. Intratumoral injection showed less number of auto-reactive T cells in the spleen than the intraperitoneal injection did. Intratumoral delivery of GITR Ab is a promising approach to induce an effective immunity compared to the systemic delivery.