Treatment of advanced tumors with agonistic anti-GITR mAb and its effects on tumor-infiltrating Foxp3+CD25+CD4+ regulatory T cells.
Treatment of advanced tumors with agonistic anti-GITR mAb and its effects on tumor-infiltrating Foxp3+CD25+CD4+ regulatory T cells.
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用激动性抗GITR mAb治疗晚期肿瘤及其对肿瘤浸润Foxp3+CD25+CD4+调节T细胞的影响。
DOI：
10.1084/jem.20050940
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发表时间：
2005-10-03
影响因子：
15.3
通讯作者：
Sakaguchi, S
中科院分区：
文献类型：
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作者：
Ko, K;Yamazaki, S;Nakamura, K;Nishioka, T;Hirota, K;Yamaguchi, T;Shimizu, J;Nomura, T;Chiba, T;Sakaguchi, S
通过糖皮质激素诱导的肿瘤坏死因子受体家族相关蛋白（GITR）刺激T细胞可以引起有效的肿瘤免疫。向荷瘤小鼠静脉内或直接向肿瘤中单次施用激动性抗GITR单克隆抗体（mAb）引起了有效的肿瘤特异性免疫并根除了已建立的肿瘤，而不引发明显的自身免疫性疾病。大量的CD 4+和CD 8 + T细胞，包括干扰素（IFN）-γ-分泌细胞，浸润消退的肿瘤。脾脏中分泌肿瘤特异性IFN-γ的CD 4+和CD 8 + T细胞也增加。该治疗导致IFN-γ完整小鼠的肿瘤排斥，但不导致IFN-γ缺陷小鼠的肿瘤排斥。此外，抗GITR和抗CTLA-4 mAb的共同施用具有协同效应，导致更晚期肿瘤的根除。相比之下，抗-CD 25和抗-GITR mAb的共同施用比单独抗-GITR治疗的有效性低，因为抗-CD 25耗尽了CD 25+活化的效应T细胞和CD 25 + CD 4+天然存在的调节性T（T reg）细胞。重要的是，表达T reg特异性转录因子Foxp 3的CD 4 + T细胞主要浸润对照小鼠中生长的肿瘤，表明肿瘤浸润的天然Foxp 3 + CD 25 + CD 4 + T reg细胞可能阻碍有效肿瘤免疫的发展。总之，通过GITR的T细胞刺激减弱了T reg介导的抑制或增强了CD 4+和CD 8+效应T细胞（包括分泌IFN-γ的那些）的肿瘤杀伤，或两者兼而有之。因此，激动性抗GITR mAb有助于治疗晚期癌症。
T cell stimulation via glucocorticoid-induced tumor necrosis factor receptor family–related protein (GITR) can evoke effective tumor immunity. A single administration of agonistic anti-GITR monoclonal antibody (mAb) to tumor-bearing mice intravenously or directly into tumors provoked potent tumor-specific immunity and eradicated established tumors without eliciting overt autoimmune disease. A large number of CD4+ and CD8+ T cells, including interferon (IFN)-γ–secreting cells, infiltrated regressing tumors. Tumor-specific IFN-γ–secreting CD4+ and CD8+ T cells also increased in the spleen. The treatment led to tumor rejection in IFN-γ–intact mice but not IFN-γ–deficient mice. Furthermore, coadministration of anti-GITR and anti–CTLA-4 mAbs had a synergistic effect, leading to eradication of more advanced tumors. In contrast, coadministration of anti-CD25 and anti-GITR mAbs was less effective than anti-GITR treatment alone, because anti-CD25 depleted both CD25+-activated effector T cells and CD25+CD4+ naturally occurring regulatory T (T reg) cells. Importantly, CD4+ T cells expressing the T reg–specific transcription factor Foxp3 predominantly infiltrated growing tumors in control mice, indicating that tumor-infiltrating natural Foxp3+CD25+CD4+ T reg cells may hamper the development of effective tumor immunity. Taken together, T cell stimulation through GITR attenuates T reg–mediated suppression or enhances tumor-killing by CD4+ and CD8+ effector T cells, including those secreting IFN-γ, or both. Agonistic anti-GITR mAb is therefore instrumental in treating advanced cancers.
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影响因子：
32.4
作者：
DIGHE, AS;RICHARDS, E;SCHREIBER, RD
通讯作者：
SCHREIBER, RD
影响因子：
4.4
作者：
Ji, HB;Liao, GX;Terhorst, C
通讯作者：
Terhorst, C
影响因子：
5.4
作者：
Tang, QZ;Boden, EK;Bluestone, JA
通讯作者：
Bluestone, JA
DOI：
10.1084/jem.20040116
发表时间：
2004-07-19
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Muriglan SJ;Ramirez-Montagut T;Alpdogan O;Van Huystee TW;Eng JM;Hubbard VM;Kochman AA;Tjoe KH;Riccardi C;Pandolfi PP;Sakaguchi S;Houghton AN;Van Den Brink MR
通讯作者：
Van Den Brink MR
DOI：
10.1084/jem.20041130
发表时间：
2004-09-20
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Turk MJ;Guevara-Patiño JA;Rizzuto GA;Engelhorn ME;Sakaguchi S;Houghton AN
通讯作者：
Houghton AN