Oncolytic Zika virus promotes intratumoral T cell infiltration and improves immunotherapy efficacy in glioblastoma

Lishu Chen; Chao Zhou; Qi Chen; Jingzhe Shang; Zhaodan Liu; Yan Guo; Chunfeng Li; HongJiang Wang; Qing Ye; XiaoFeng Li; Shulong Zu; Fangye Li; Qing Xia; Tao Zhou; Ailing Li; Chenhui Wang; Yun Chen; Aiping Wu; Chengfeng Qin; Jianghong Man

doi:10.1016/j.omto.2022.01.011

Oncolytic Zika virus promotes intratumoral T cell infiltration and improves immunotherapy efficacy in glioblastoma

Mol Ther Oncolytics. 2022 Feb 1:24:522-534. doi: 10.1016/j.omto.2022.01.011. eCollection 2022 Mar 17.

Authors

Lishu Chen¹, Chao Zhou^{2

3

4}, Qi Chen³, Jingzhe Shang^{5

6}, Zhaodan Liu¹, Yan Guo³, Chunfeng Li^{3

5}, HongJiang Wang³, Qing Ye³, XiaoFeng Li³, Shulong Zu^{3

5

6}, Fangye Li⁷, Qing Xia¹, Tao Zhou¹, Ailing Li¹, Chenhui Wang⁸, Yun Chen^{2

4}, Aiping Wu^{5

6}, Chengfeng Qin³, Jianghong Man¹

Affiliations

¹ State Key Laboratory of Proteomics, National Center of Biomedical Analysis, Beijing 100850, China.
² Department of Immunology, Key Laboratory of Immune Microenvironment and Disease, Nanjing Medical University, Nanjing 211166, China.
³ State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, AMMS, Beijing 100071, China.
⁴ Jiangsu Key Lab of Cancer Biomarkers, Prevention, and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing 211166, China.
⁵ Suzhou Institute of Systems Medicine, Suzhou, Jiangsu 215123, China.
⁶ Center for Systems Medicine, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100005, China.
⁷ Department of Neurosurgery, First Medical Center of PLA General Hospital, Beijing 100853, China.
⁸ Key Laboratory of Molecular Biophysics of the Ministry of Education, National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, China.

Abstract

Glioblastoma (GBM) is the deadliest primary brain tumor and is generally resistant to immunotherapy because of severe dysfunction of T cells. Novel treatment options are critically needed to overcome the immunotherapy resistance of GBM. Here we demonstrate that Zika virus (ZIKV) treatment improves the efficacy of anti-PD ligand 1 (PD-L1) immunotherapy in GBM. We found that ZIKV induces a strong pro-inflammatory response and increases CD4⁺ and CD8⁺ T cell intratumoral infiltration and activation in GBM mouse models. ZIKV treatment of mice bearing GBM tumors inhibits tumor growth and prolongs survival. These therapeutic effects of ZIKV on GBM tumors are negated in mice depleted of T cells. Moreover, ZIKV dramatically promotes activation of the type I interferon signaling pathway in GBM cells. ZIKV treatment potently sensitizes GBM to PD-L1 blockade and provides significant and durable survival benefits. Our findings reveal that ZIKV overcomes the resistance of GBM to immune checkpoint blockade, which may lead to therapeutic applications of ZIKV in individuals with GBM receiving immunotherapy.

Keywords: CD8 T cells; PD-L1 blockade; Zika virus (ZIKV); glioblastoma; immunotherapy; oncolytic virus.