Piperlongumine conquers temozolomide chemoradiotherapy resistance to achieve immune cure in refractory glioblastoma via boosting oxidative stress-inflamation-CD8+-T cell immunity

Journal of Experimental & Clinical Cancer Research

Research

Xuan Cao¹  Hai-feng Jiang²  Song-lin Yin²  Xiao Qian Chen²  Xiao-hong Xu²  Cheng Miao²  Ting-ting Zhang²  Pan-pan Gao²  Shi-jie Xu²  Jing-yi Peng²  Jia-xing Wu²  Feng Liu³  Ximiao He⁴  Qian Zhou⁴  Feng Pan⁵ 

[1] Department of Basic Medical Science, Medical College, Taizhou University, 318000, Taizhou, China;Department of Pathophysiology, School of Basic Medicine, Tongji Medical College, Key Laboratory of Ministry of Education for Neurological Disorders, Huazhong University of Science and Technology, 430030, Wuhan, China;Department of Pathophysiology, School of Basic Medicine, Tongji Medical College, Key Laboratory of Ministry of Education for Neurological Disorders, Huazhong University of Science and Technology, 430030, Wuhan, China;Department of Pharmacy, First Affiliated Hospital of Yangtze University, 434000, Jingzhou, China;Department of Physiology, School of Basic Medicine, Tongji Medical College, Hubei Key Laboratory of Drug Target Research and Pharmacodynamic Evaluation, Huazhong University of Science and Technology, 430030, Wuhan, China;Department of Urology, Tongji Medical College, Union Hospital, Huazhong University of Science and Technology, 430022, Wuhan, China;

关键词: Piperlongumine;    Glioma;    Tumor microenvironment;    ROS generation/elimination;    Immunotherapy;    PD-1;   

DOI  :  10.1186/s13046-023-02686-1

 received in 2023-01-11, accepted in 2023-04-26,  发布年份 2023

来源: Springer

【 摘 要 】

BackgroundThe 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.MethodsSyngeneic 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.ResultsHere 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.ConclusionOur 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.

【 授权许可】

CC BY   
© The Author(s) 2023

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