Cancer Metabolism

Targeting aerobic glycolysis by dichloroacetate improves Newcastle disease virus-mediated viro-immunotherapy in hepatocellular carcinoma

Abstract

Background

Oncolytic viro-immunotherapy holds promise for cancer treatment. While immune activation can be robustly triggered by oncolytic viruses, negative feedback is often upregulated in the tumour microenvironment (TME). Lactate accumulation, signal transducer and activator of transcription 3 (STAT3) activation, indoleamine 2,3-dioxygenase 1 (IDO1) expression, and myeloid-derived suppressor cell (MDSC) infiltration coordinate to shape the immunosuppressive TME.

Methods

Representative hepatocellular carcinoma (HCC) cell lines and HCC-bearing mice were treated with oncolytic Newcastle disease virus (NDV), alone or in combination with dichloroacetate (DCA, a pyruvate dehydrogenase kinase (PDK) inhibitor).

Results

We found that infection with oncolytic NDV led to significant induction of the aforementioned suppressive factors. Interestingly, DCA significantly reduced lactate release, STAT3 activation, IDO1 upregulation, and MDSC infiltration in NDV-treated HCC. Consequently, DCA significantly enhanced the antitumour immune responses, leading to improved antitumour efficacy and prolonged survival in mouse models of ascitic and subcutaneous HCC. Furthermore, DCA increased NDV replication in a PDK-1-dependent manner in HCC.

Conclusions

Targeting aerobic glycolysis by DCA improves NDV-mediated viro-immunotherapy in HCC by mitigating immune negative feedback and promoting viral replication. These findings provide a rationale for targeting reprogrammed metabolism together with oncolytic virus-mediated viro-immunotherapy for HCC treatment.

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Acknowledgements

We thank Prof. Y. Wang (Jiangsu Academy of Agricultural Sciences, China) for providing the NDV La Sota strain, and Translational Medicine Core Facilities of Nanjing University for instrumental support.

Author information

J.W. and G.M. designed the study; G.M., B.L., J.W. and J.D. developed the methods; G.M., B.L., A.C., M.Z., T.X. and H.Z. performed the experiments; G.M., B.L. and J.D. analysed the data; G.M. and J.W. wrote and revised the manuscript; J.W. and D.Y. supervised this study; J.W., D.Y., J.D. and G.M. acquired the funding for this study.

Correspondence to Decai Yu or Jiwu Wei.

Ethics declarations

Competing interests

The authors declare no competing interests.

Ethics approval and consent to participate

All animal experiments were conducted with the approval of the Ethics Committee of the Affiliated Drum Tower Hospital of Nanjing University Medical School. Animal welfare was closely monitored in accordance with the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. The human HCC cell line HCCLM3 and mouse HCC cell line H22 were acquired from the China Center for Type Culture Collection (Wuhan, China), the mouse HCC cell line Hepa1-6 was acquired from Cell Bank of Type Culture Collection Chinese Academy of Sciences (Shanghai, China).

Funding

This work was supported by the National Natural Science Foundation of China (81773255, 81700037, 81871967, and 81903147), the Natural Science Foundation of Jiangsu Province of China (BK20171098), Social Development Foundation of Jiangsu Province of China (BE2018604), Six talent peaks project in Jiangsu Province to J.W., Jiangsu Provincial Medical Talent to D.Y., and Project funded by China Postdoctoral Science Foundation (2018M642223).

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Not applicable.

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All data and materials generated during and/or analysed during the current study are available from the corresponding author on reasonable request.

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Meng, G., Li, B., Chen, A. et al. Targeting aerobic glycolysis by dichloroacetate improves Newcastle disease virus-mediated viro-immunotherapy in hepatocellular carcinoma. Br J Cancer 122, 111–120 (2020). https://doi.org/10.1038/s41416-019-0639-7

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