Suppression of Tregs by anti-glucocorticoid induced TNF receptor antibody enhances the antitumor immunity of interferon-α gene therapy for pancreatic cancer.
Suppression of Tregs by anti-glucocorticoid induced TNF receptor antibody enhances the antitumor immunity of interferon-α gene therapy for pancreatic cancer.
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DOI：
10.1111/cas.12332
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发表时间：
2014-02
期刊：
影响因子：
5.7
通讯作者：
Aoki K
中科院分区：
文献类型：
--
作者：
Aida K;Miyakawa R;Suzuki K;Narumi K;Udagawa T;Yamamoto Y;Chikaraishi T;Yoshida T;Aoki K
我们已经报道了干扰素（IFN）-α可以通过多种抗肿瘤机制攻击癌细胞，包括诱导直接癌细胞死亡和增强几种胰腺癌模型中的免疫应答。然而，肿瘤中的免疫耐受微环境通常是癌症免疫治疗失败的原因。在这里，我们研究了是否抑制肿瘤内的调节性T细胞（TCRs）可以增强肿瘤内IFN-α基因转移诱导的抗肿瘤免疫。首先，我们表明，腹腔内施用激动性抗糖皮质激素诱导的TNF受体（GITR）单克隆抗体（mAb），据报道其抑制TcB的功能，显著抑制小鼠胰腺癌模型中的皮下肿瘤生长。然后将抗GITR mAb与IFN-α-腺病毒载体的瘤内注射组合。用抗体治疗不仅在载体注射的肿瘤中而且在载体未注射的肿瘤中协同增强IFN-α基因治疗的抗肿瘤效果。免疫组化结果显示，抗GITR单抗可减少Foxp 3+细胞在肿瘤中的浸润，而IFN-α基因转染可增加肿瘤中的CD 4+和CD 8 + T细胞。因此，联合治疗强烈地使肿瘤微环境的免疫平衡向抗肿瘤方向倾斜，导致显著的全身抗肿瘤作用。在抗体处理的小鼠中，TcR上的CCR 5表达下调，这可以解释肿瘤浸润性TcR的减少。GITR mAb抑制Treg表达与IFN-α基因治疗联合诱导肿瘤免疫可能是胰腺癌治疗的一个有前景的策略。
We have reported that interferon (IFN)-α can attack cancer cells by multiple antitumor mechanisms including the induction of direct cancer cell death and the enhancement of an immune response in several pancreatic cancer models. However, an immunotolerant microenvironment in the tumors is often responsible for the failure of the cancer immunotherapy. Here we examined whether the suppression of regulatory T cells (Tregs) within tumors can enhance an antitumor immunity induced by an intratumoral IFN-α gene transfer. First we showed that an intraperitoneal administration of an agonistic anti-glucocorticoid induced TNF receptor (GITR) monoclonal antibody (mAb), which is reported to suppress the function of Tregs, significantly inhibited subcutaneous tumor growth in a murine pancreatic cancer model. The anti-GITR mAb was then combined with the intratumoral injection of the IFN-α-adenovirus vector. The treatment with the antibody synergistically augmented the antitumor effect of IFN-α gene therapy not only in the vector-injected tumors but also in the vector-uninjected tumors. Immunostaining showed that the anti-GITR mAb decreased Foxp3+ cells infiltrating in the tumors, while the intratumoral IFN-α gene transfer increased CD4+ and CD8+ T cells in the tumors. Therefore, the combination therapy strongly inclined the immune balance of the tumor microenvironment in an antitumor direction, leading to a marked systemic antitumor effect. The CCR5 expression on Tregs was downregulated in the antibody-treated mice, which may explain the decrease of tumor-infiltrating Tregs. The combination of Treg-suppression by GITR mAb and the tumor immunity induction by IFN-α gene therapy could be a promising therapeutic strategy for pancreatic cancer.
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DOI：
10.4049/jimmunol.182.3.1746
发表时间：
2009-02-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Tan MC;Goedegebuure PS;Belt BA;Flaherty B;Sankpal N;Gillanders WE;Eberlein TJ;Hsieh CS;Linehan DC
通讯作者：
Linehan DC
影响因子：
2.4
作者：
Rosenblatt, Jacalyn;McDermott, David F.
通讯作者：
McDermott, David F.
DOI：
10.1073/pnas.0509182102
发表时间：
2005-12-20
影响因子：
11.1
作者：
Sato, E;Olson, SH;Odunsi, K
通讯作者：
Odunsi, K
影响因子：
5.7
作者：
Hara, Hidehiko;Kobayashi, Akihiko;Aoki, Kazunori
通讯作者：
Aoki, Kazunori
影响因子：
2.3
作者：
Hackert, Thilo;Buechler, Markus W.
通讯作者：
Buechler, Markus W.