PD-L1 promotes oncolytic virus infection via a metabolic shift that inhibits the type I IFN pathway
Jonathan J Hodgins1,2,3, John Abou-Hamad1,4, Colin Edward O'Dwyer1,2,3
1Cancer Therapeutics Program, Ottawa Hospital Research Institute , Ottawa, Canada.
Abstract:
While conventional wisdom initially postulated that PD-L1 serves as the inert ligand for PD-1, an emerging body of literature suggests that PD-L1 has cell-intrinsic functions in immune and cancer cells. In line with these studies, here we show that engagement of PD-L1 via cellular ligands or agonistic antibodies, including those used in the clinic, potently inhibits the type I interferon pathway in cancer cells. Hampered type I interferon responses in PD-L1-expressing cancer cells resulted in enhanced efficacy of oncolytic viruses in vitro and in vivo. Consistently, PD-L1 expression marked tumor explants from cancer patients that were best infected by oncolytic viruses. Mechanistically, PD-L1 promoted a metabolic shift characterized by enhanced glycolysis rate that resulted in increased lactate production. In turn, lactate inhibited type I IFN responses. In addition to adding mechanistic insight into PD-L1 intrinsic function, our results will also help guide the numerous ongoing efforts to combine PD-L1 antibodies with oncolytic virotherapy in clinical trials.
Insights
Programmed death-ligand 1 (PD-L1) has intrinsic functions that inhibit cancer cell type I interferon responses. This inhibition enhances oncolytic virus efficacy, suggesting new therapeutic strategies.
Area of Science:
- Immunology
- Cancer Biology
- Virology
Background:
- Programmed death-ligand 1 (PD-L1) was traditionally viewed as an inert ligand for PD-1.
- Emerging evidence indicates PD-L1 possesses cell-intrinsic functions within immune and cancer cells.
Purpose of the Study:
- To investigate the intrinsic functions of PD-L1 in cancer cells.
- To determine the impact of PD-L1 engagement on type I interferon (IFN) pathways.
- To evaluate the effect of PD-L1-mediated inhibition on oncolytic virus efficacy.
Main Methods:
- Engagement of PD-L1 using cellular ligands and agonistic antibodies.
- Assessment of type I IFN pathway activity in cancer cells.
- In vitro and in vivo evaluation of oncolytic virus efficacy in PD-L1 expressing cancer models.
- Analysis of tumor explants from cancer patients for PD-L1 expression and oncolytic virus infectivity.
- Metabolic profiling to identify PD-L1-associated metabolic shifts.
Main Results:
- Engagement of PD-L1 potently inhibits the type I interferon pathway in cancer cells.
- Impaired type I IFN responses in PD-L1-expressing cancer cells led to enhanced oncolytic virus efficacy.
- PD-L1 expression correlated with better oncolytic virus infection in patient tumor explants.
- PD-L1 promoted a metabolic shift towards increased glycolysis and lactate production.
- Lactate was identified as an inhibitor of type I IFN responses.
Conclusions:
- PD-L1 exhibits intrinsic functions that suppress type I interferon responses in cancer cells.
- PD-L1-mediated metabolic reprogramming contributes to immune evasion by inhibiting IFN pathways.
- Combining PD-L1 targeting therapies with oncolytic virotherapy holds significant therapeutic potential.
- These findings provide mechanistic insights and guidance for clinical trials combining PD-L1 antibodies and oncolytic viruses.
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