[HTML][HTML] Targeting aerobic glycolysis by dichloroacetate improves Newcastle disease virus-mediated viro-immunotherapy in hepatocellular carcinoma
British Journal of Cancer, 2020•nature.com
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 …
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 …
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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