Piperlongumine conquers temozolomide chemoradiotherapy resistance to achieve immune cure in refractory glioblastoma via boosting oxidative stress-inflamation-CD8(+)-T cell immunity.
Piperlongumine conquers temozolomide chemoradiotherapy resistance to achieve immune cure in refractory glioblastoma via boosting oxidative stress-inflamation-CD8(+)-T cell immunity.
复制标题
阿洛格明通过增强氧化应激-炎症-CD 8（+）-T细胞免疫力，克服替莫唑胺放化疗耐药性，实现难治性胶质母细胞瘤的免疫治愈。
DOI：
10.1186/s13046-023-02686-1
复制
发表时间：
2023-05-10
期刊：
影响因子：
--
通讯作者：
中科院分区：
文献类型：
--
作者：
在临床前动物模型中有效的新疗法的失败在很大程度上反映了当前模型不能真正模拟胶质母细胞瘤（GBM）的病理/治疗特征的事实，其中最有效的替莫唑胺放化疗（RT/TMZ）方案只能略微延长生存期。如何提高RT/TMZ的疗效仍是临床面临的主要挑战。对同系G422 TN-GBM模型小鼠分别进行RT/TMZ、手术、哌隆单胺（PL）、α PD 1、谷胱甘肽等治疗。来自G422 TN-GBM和人GBM的代谢组学或转录组学数据用于基因富集分析和ROS产生/清除平衡、氧化应激损伤、炎症和免疫细胞浸润的估计。总生存率、生物发光成像、免疫组织化学和免疫荧光染色用于检查治疗效果和作用机制。在这里，我们确定了在真正难治性和可靠的小鼠三阴性GBM（G422 TN）临床前模型中，在RT/TMZ治疗后的代谢组学分析中谷胱甘肽代谢发生了最显著的改变。一致的是，ROS发生器/清除剂在G422 TN肿瘤和人GBM中高度失调。ROS诱导剂PL协同手术/TMZ、手术/RT/TMZ或RT/TMZ以在G422 TN小鼠中实现长期存活（LTS），但来自RT/TMZ/PL治疗的仅一只LTS小鼠通过了再激发阶段（免疫治愈）。此外，RT/TMZ/PL联合抗PD-1抗体（α PD 1）的免疫治疗使LTS（50%）和免疫治愈（25%）小鼠加倍。谷氨酸完全消除PL-协同效应。从机制上讲，ROS减少与RT/TMZ抗性相关。在RT/TMZ方案的基础上，PL通过逆转Duox 2/Gpx 2恢复G422肿瘤细胞内ROS水平，激活氧化应激/炎症/免疫应答信号基因，抑制肿瘤细胞增殖/侵袭，增加肿瘤细胞凋亡和CD 3 +/CD 4 +/CD 8 + T淋巴细胞。我们的研究结果表明，PL逆转RT/TMZ减少的ROS，并协同重置肿瘤微环境，以治愈GBM。RT/TMZ/PL或RT/TMZ/PL/α PD 1对难治性GBM有较好的免疫治疗作用，值得临床研究。在线版本包含补充材料，可通过10.1186/s13046-023-02686-1获得。
The failure of novel therapies effective in preclinical animal models largely reflects the fact that current models do not really mimic the pathological/therapeutic features of glioblastoma (GBM), in which the most effective temozolomide chemoradiotherapy (RT/TMZ) regimen can only slightly extend survival. How to improve RT/TMZ efficacy remains a major challenge in clinic. Syngeneic G422TN-GBM model mice were subject to RT/TMZ, surgery, piperlongumine (PL), αPD1, glutathione. Metabolomics or transcriptomics data from G422TN-GBM and human GBM were used for gene enrichment analysis and estimation of ROS generation/scavenging balance, oxidative stress damage, inflammation and immune cell infiltration. Overall survival, bioluminescent imaging, immunohistochemistry, and immunofluorescence staining were used to examine therapeutic efficacy and mechanisms of action. Here we identified that glutathione metabolism was most significantly altered in metabolomics analysis upon RT/TMZ therapies in a truly refractory and reliable mouse triple-negative GBM (G422TN) preclinical model. Consistently, ROS generators/scavengers were highly dysregulated in both G422TN-tumor and human GBM. The ROS-inducer PL synergized surgery/TMZ, surgery/RT/TMZ or RT/TMZ to achieve long-term survival (LTS) in G422TN-mice, but only one LTS-mouse from RT/TMZ/PL therapy passed the rechallenging phase (immune cure). Furthermore, the immunotherapy of RT/TMZ/PL plus anti-PD-1 antibody (αPD1) doubled LTS (50%) and immune-cured (25%) mice. Glutathione completely abolished PL-synergistic effects. Mechanistically, ROS reduction was associated with RT/TMZ-resistance. PL restored ROS level (mainly via reversing Duox2/Gpx2), activated oxidative stress/inflammation/immune responses signature genes, reduced cancer cell proliferation/invasion, increased apoptosis and CD3+/CD4+/CD8+ T-lymphocytes in G422TN-tumor on the basis of RT/TMZ regimen. Our findings demonstrate that PL reverses RT/TMZ-reduced ROS and synergistically resets tumor microenvironment to cure GBM. RT/TMZ/PL or RT/TMZ/PL/αPD1 exacts effective immune cure in refractory GBM, deserving a priority for clinical trials. The online version contains supplementary material available at 10.1186/s13046-023-02686-1.
登录
查看更多内容
通过阻断小胶质细胞和癌细胞之间的 Wnt 信号传导重新编程 IDH1 野生型胶质母细胞瘤的免疫抑制微环境
影响因子：
7.2
作者：
Fan D;Yue Q;Chen J;Wang C;Yu R;Jin Z;Yin S;Wang Q;Chen L;Liao X;Peng C;Zhang J;Cao Z;Mao Y;Huang R;Chen L;Li C
通讯作者：
Li C
影响因子：
28.5
作者：
Lei K;Gu X;Alvarado AG;Du Y;Luo S;Ahn EH;Kang SS;Ji B;Liu X;Mao H;Fu H;Kornblum HI;Jin L;Li H;Ye K
通讯作者：
Ye K
DOI：
10.1084/jem.20130678
发表时间：
2013-12-16
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Vom Berg J;Vrohlings M;Haller S;Haimovici A;Kulig P;Sledzinska A;Weller M;Becher B
通讯作者：
Becher B
影响因子：
15.9
作者：
Panagioti, Eleni;Kurokawa, Cheyne;Galanis, Evanthia
通讯作者：
Galanis, Evanthia
影响因子：
82.9
作者：
通讯作者：
--