Oncolytic Newcastle disease virus induces autophagy-dependent immunogenic cell death in lung cancer cells

Tian Ye; Ke Jiang; Liwen Wei; Martin P Barr; Qing Xu; Guirong Zhang; Chan Ding; Songshu Meng; Haozhe Piao

Oncolytic Newcastle disease virus induces autophagy-dependent immunogenic cell death in lung cancer cells

Am J Cancer Res. 2018 Aug 1;8(8):1514-1527. eCollection 2018.

Authors

Tian Ye^{1

2

3}, Ke Jiang³, Liwen Wei¹, Martin P Barr⁴, Qing Xu^{5

6

7}, Guirong Zhang², Chan Ding⁸, Songshu Meng³, Haozhe Piao¹

Affiliations

¹ Department of Neurosurgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute Shenyang, China.
² Central Laboratory, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute Shenyang, China.
³ Institute of Cancer Stem Cell, Dalian Medical University Dalian, China.
⁴ Thoracic Oncology Research Group, Trinity Translational Medicine Institute, Trinity Centre for Health Sciences St. James's Hospital & Trinity College Dublin Dublin, Ireland.
⁵ Department of Oncology, Shanghai Tenth People's Hospital, Tongji University Shanghai, China.
⁶ Tongji University Cancer Center Shanghai, China.
⁷ Department of Oncology, Dermatology Hospital, Tongji University Shanghai, China.
⁸ Department of Avian Infectious Diseases, Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Science Shanghai, China.

PMID: 30210920
PMCID: PMC6129498

Abstract

In addition to direct oncolysis, oncolytic viruses trigger immunogenic cell death (ICD) and primes antitumor immunity. We have previously shown that oncolytic Newcastle disease virus (NDV), strain FMW (NDV/FMW), induces apoptosis and/or autophagy in cancer cells. In this study, we investigated whether oncolytic NDV can induce ICD in lung cancer cells and whether apoptosis or autophagy plays a role in NDV-triggered ICD. To this end, we examined cell surface expression of calreticulin (CRT) on NDV-infected lung cancer cells and measured ICD determinants, high mobility group box 1 (HMGB1), heat shock protein 70/90 (HSP70/90) and ATP in supernatants following viral infection. Flow cytometric analysis using anti-CRT antibody and PI staining of NDV-infected lung cancer cells showed an increase in the number of viable (propidium iodide-negative) cells, suggesting the induction of CRT exposure upon NDV infection. In addition, confocal and immunoblot analysis using anti-CRT antibody showed that an enhanced accumulation of CRT on the cell surface of NDV-infected cells, indicating the translocation of CRT to the cell membrane upon NDV infection. We further demonstrated that NDV infection induced the release of secreted HMGB1 and HSP70/90 by examining the concentrated supernatants of NDV-infected cells. Furthermore, pre-treatment with either the pan-caspase inhibitor z-VAD-FMK or the necrosis inhibitor Necrostain-1, had no impact on NDV-induced release of ICD determinants in lung cancer cells. Rather, depletion of autophagy-related genes in lung cancer cells significantly inhibited the induction of ICD determinants by NDV. Of translational importance, in a lung cancer xenograft model, treatment of mice with supernatants from NDV-infected cells significantly inhibited tumour growth. Together, these results indicate that oncolytic NDV is a potent ICD-inducer and that autophagy contributes to NDV-mediated induction of ICD in lung cancer cells.

Keywords: Newcastle disease virus; apoptosis; autophagy; immunogenic cell death; lung cancer.