Bypassing STAT3-mediated inhibition of the transcriptional regulator ID2 improves the antitumor efficacy of dendritic cells.
Bypassing STAT3-mediated inhibition of the transcriptional regulator ID2 improves the antitumor efficacy of dendritic cells.
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绕过STAT3介导的对转录调节因子ID2的抑制可提高树突状细胞的抗肿瘤功效。
DOI：
10.1126/scisignal.aaf3957
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发表时间：
2016-09-27
影响因子：
7.3
通讯作者：
Watowich SS
中科院分区：
文献类型：
--
作者：
Li HS;Liu C;Xiao Y;Chu F;Liang X;Peng W;Hu J;Neelapu SS;Sun SC;Hwu P;Watowich SS
尽管树突状细胞（DCs）具有刺激淋巴细胞反应和宿主免疫的强大能力，但粒细胞-巨噬细胞集落刺激因子（GM-CSF）衍生的树突状细胞（GM-DCs）作为抗肿瘤疫苗在癌症免疫治疗中显示出相对适度的成功。我们发现，将gm - dc注射到小鼠黑色素瘤肿瘤中，或将gm - dc与黑色素瘤分泌的细胞因子或黑色素瘤条件培养基一起培养，可以迅速抑制dc内在基因编码分化抑制因子2 （ID2）的表达，这是一种转录调节因子。黑色素瘤相关细胞因子通过激活信号换能器和转录激活因子3 （STAT3）抑制小鼠dc中Id2的转录。在gm - dc中强制表达ID2 （ID2- gm - dc）可抑制促炎细胞因子TNF-α的产生。接种id2 - gm - dc可以减缓黑色素瘤的进展，提高动物存活率，这与肿瘤浸润性干扰素-γ阳性CD4+效应细胞和CD8+细胞毒性T细胞的丰度增加以及肿瘤浸润性调节性CD4+ T细胞的数量减少有关。通过与程序性细胞死亡蛋白1 （PD-1）的阻断抗体联合治疗，ID2-GM-DC疫苗的疗效得到改善，PD-1是目前克服免疫检查点信号抑制的免疫疗法。总的来说，我们的数据揭示了dc中先前未被识别的stat3介导的免疫抑制机制，并表明dc固有的ID2通过调节肿瘤相关的CD4+ T细胞反应来促进肿瘤免疫。因此，在DC中选择性抑制STAT3或过表达ID2可能提高DC疫苗在癌症治疗中的效率。
Despite the potent ability of dendritic cells (DCs) to stimulate lymphocyte responses and host immunity, granulocyte-macrophage colony-stimulating factor (GM-CSF)-derived DCs (GM-DCs) used as antitumor vaccines have demonstrated relatively modest success in cancer immunotherapy. We found that injecting GM-DCs into melanoma tumors in mice, or culturing GM-DCs with melanoma-secreted cytokines or melanoma-conditioned medium, rapidly suppressed DC-intrinsic expression of the gene encoding inhibitor of differentiation 2 (ID2), a transcriptional regulator. Melanoma-associated cytokines repressed Id2 transcription in murine DCs through the activation of signal transducer and activator of transcription 3 (STAT3). Enforced expression of ID2 in GM-DCs (ID2-GM-DCs) suppressed their production of the pro-inflammatory cytokine TNF-α. Vaccination with ID2-GM-DCs slowed the progression of melanoma tumors and enhanced animal survival, which was associated with an increased abundance of tumor-infiltrating interferon-γ-positive CD4+ effector and CD8+ cytotoxic T cells and a decreased number of tumor-infiltrating regulatory CD4+ T cells. The efficacy of the ID2-GM-DC vaccine was improved by combinatorial treatment with a blocking antibody to programmed cell death protein 1 (PD-1), a current immunotherapy that overcomes suppressive immune checkpoint signaling. Collectively, our data reveal a previously unrecognized STAT3-mediated immunosuppressive mechanism in DCs and indicate that DC-intrinsic ID2 promotes tumor immunity by modulating tumor-associated CD4+ T cell responses. Thus inhibiting STAT3 or overexpressing ID2 selectively in DCs may improve the efficiency of DC vaccines in cancer therapy.
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DOI：
10.1084/jem.20062648
发表时间：
2007-07-09
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Caton ML;Smith-Raska MR;Reizis B
通讯作者：
Reizis B
影响因子：
30.5
作者：
Bedoui, Sammy;Whitney, Paul G.;Heath, William R.
通讯作者：
Heath, William R.
DOI：
10.1158/1078-0432.ccr-14-3145
发表时间：
2015-08-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Hossain DM;Pal SK;Moreira D;Duttagupta P;Zhang Q;Won H;Jones J;D'Apuzzo M;Forman S;Kortylewski M
通讯作者：
Kortylewski M
影响因子：
2.8
作者：
Kamphorst AO;Ahmed R
通讯作者：
Ahmed R
影响因子：
11.4
作者：
Jackson, Jacob T.;Hu, Yifang;Liu, Ruijie;Masson, Frederick;D'Amico, Angela;Carotta, Sebastian;Xin, Annie;Camilleri, Mary J.;Mount, Adele M.;Kallies, Axel;Wu, Li;Smyth, Gordon K.;Nutt, Stephen L.;Belz, Gabrielle T.
通讯作者：
Belz, Gabrielle T.