Arsenic trioxide elicits prophylactic and therapeutic immune responses against solid tumors by inducing necroptosis and ferroptosis

扫码查看

原文链接

万方数据

外文摘要：Boosting tumor immunosurveillance with vaccines has been proven to be a feasible and cost-effective strategy to fight cancer.Although major breakthroughs have been achieved in preventative tumor vaccines targeting oncogenic viruses,limited advances have been made in curative vaccines for virus-irrelevant malignancies.Accumulating evidence suggests that preconditioning tumor cells with certain cytotoxic drugs can generate whole-cell tumor vaccines with strong prophylactic activities.However,the immunogenicity of these vaccines is not sufficient to restrain the outgrowth of existing tumors.In this study,we identified arsenic trioxide(ATO)as a wide-spectrum cytotoxic and highly immunogenic drug through multiparameter screening.ATO preconditioning could generate whole-cell tumor vaccines with potent antineoplastic effects in both prophylactic and therapeutic settings.The tumor-preventive or tumor-suppressive benefits of these vaccines relied on CD8+ T cells and type I and II interferon signaling and could be linked to the release of immunostimulatory danger molecules.Unexpectedly,following ATO-induced oxidative stress,multiple cell death pathways were activated,including autophagy,apoptosis,necroptosis,and ferroptosis.CRISPR‒Cas9-mediated knockout of cell death executors revealed that the absence of Rip3,Mlkl,or Acsl4 largely abolished the efficacy of ATO-based prophylactic and therapeutic cancer vaccines.This therapeutic failure could be rescued by coadministration of danger molecule analogs.In addition,PD-1 blockade synergistically improved the therapeutic efficacy of ATO-based cancer vaccines by augmenting local IFN-γ production.

外文关键词：

Tumor vaccineArsenic trioxideNecroptosisFerroptosisImmunosurveillance

作者：

Jinfeng Chen、Ziqi Jin、Shuqing Zhang、Xiao Zhang、Peipei Li、Heng Yang、Yuting Ma

展开 >

作者单位：

Institute of Systems Medicine,Chinese Academy of Medical Sciences&Peking Union Medical College,Beijing 10005,China

Suzhou Institute of Systems Medicine,Suzhou,Jiangsu 215123,China

National Key Laboratory of Medical Immunology,Shanghai 200433,China

Collaborative Innovation Center for Cancer Personalized Medicine,Nanjing Medical University,Nanjing 211166,China

展开 >

基金：

National Science and Technology Innovation 2030 Major Project of ChinaNatural Science Foundation of ChinaNatural Science Foundation of ChinaCAMS Innovation Fund for Medical SciencesCAMS Innovation Fund for Medical SciencesCAMS Innovation Fund for Medical SciencesNational Special Support Program for Highlevel TalentsChina Ministry of Science and Technology(National Key Research and Development Program)Innovative and Entrepreneurial Team Program(Jiangsu Province)

项目编号：

2022ZD0205700NSFC81972701CIFMS2021-I2M-1-0742022-I2M-2-0042017YFA0506200

出版年：

2023

DOI：

10.1038/s41423-022-00956-0

中国免疫学杂志(英文版)

中国免疫学会

中国免疫学杂志(英文版)

CSTPCDCSCDSCI

影响因子：0.731

ISSN：1672-7681

年,卷(期)：2023.20(1)

参考文献量50