Bleomycin exerts ambivalent antitumor immune effect by triggering both immunogenic cell death and proliferation of regulatory T cells.
Bleomycin exerts ambivalent antitumor immune effect by triggering both immunogenic cell death and proliferation of regulatory T cells.
复制标题
DOI：
10.1371/journal.pone.0065181
复制
发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Mignot G
中科院分区：
文献类型：
--
作者：
Bugaut H;Bruchard M;Berger H;Derangère V;Odoul L;Euvrard R;Ladoire S;Chalmin F;Végran F;Rébé C;Apetoh L;Ghiringhelli F;Mignot G
博来霉素（BLM）是目前用于治疗睾丸癌和霍奇金淋巴瘤的抗癌药物。这种药物通过其产生自由基氧（ROS）的能力引发癌细胞死亡。然而，尚未评估抗癌免疫反应对BLM疗效的推定贡献。我们在此观察到BLM诱导免疫原性细胞死亡。特别是，BLM能够诱导ROS介导的网状应激和自噬，这导致分子伴侣（包括钙网蛋白和ERp 57）的表面暴露，以及HMBG 1和ATP的释放。BLM诱导的抗肿瘤免疫依赖于钙网蛋白、CD 8 + T细胞和干扰素-γ。我们还发现，除了其触发免疫原性细胞死亡的能力之外，BLM通过其诱导肿瘤细胞分泌转化生长因子β（TGFβ）的能力诱导Foxp 3+调节性T（Treg）细胞的扩增。因此，Treg细胞或TGFβ耗竭显著增强BLM的抗肿瘤作用。我们得出结论，BLM诱导抗肿瘤CD 8 + T细胞应答和对抗Treg增殖。未来，在BLM治疗期间抑制TGFβ或Treg可以大大增强BLM抗肿瘤功效。
Bleomycin (BLM) is an anticancer drug currently used for the treatment of testis cancer and Hodgkin lymphoma. This drug triggers cancer cell death via its capacity to generate radical oxygen species (ROS). However, the putative contribution of anticancer immune responses to the efficacy of BLM has not been evaluated. We make here the observation that BLM induces immunogenic cell death. In particular, BLM is able to induce ROS-mediated reticulum stress and autophagy, which result in the surface exposure of chaperones, including calreticulin and ERp57, and liberation of HMBG1 and ATP. BLM induces anti-tumor immunity which relies on calreticulin, CD8+ T cells and interferon-γ. We also find that, in addition to its capacity to trigger immunogenic cell death, BLM induces expansion of Foxp3+ regulatory T (Treg) cells via its capacity to induce transforming growth factor beta (TGFβ) secretion by tumor cells. Accordingly, Treg cells or TGFβ depletion dramatically potentiates the antitumor effect of BLM. We conclude that BLM induces both anti-tumor CD8+ T cell response and a counteracting Treg proliferation. In the future, TGFβ or Treg inhibition during BLM treatment could greatly enhance BLM anti-tumor efficacy.
登录
查看更多内容
影响因子：
64.8
作者：
Bettelli, E;Carrier, YJ;Kuchroo, VK
通讯作者：
Kuchroo, VK
影响因子：
32.4
作者：
Chalmin, Fanny;Mignot, Gregoire;Ghiringhelli, Francois
通讯作者：
Ghiringhelli, Francois
影响因子：
4.4
作者：
Melencio, Louise;McKallip, Robert J.;Nagarkatti, Mitzi
通讯作者：
Nagarkatti, Mitzi
DOI：
10.1513/pats.200605-125sf
发表时间：
2006-11-01
期刊：
Proceedings of the American Thoracic Society
影响因子：
--
作者：
Gauldie, Jack;Kolb, Martin;Warburton, David
通讯作者：
Warburton, David
影响因子：
4.4
作者：
Huber, S;Schramm, C;Blessing, M
通讯作者：
Blessing, M