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Status |
Public on Jun 28, 2023 |
Title |
More than a ligand: PD-L1 promotes oncolytic virus infection via a metabolic shift that inhibits the type I interferon pathway |
Organism |
Mus musculus |
Experiment type |
Expression profiling by high throughput sequencing
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Summary |
Targeting the PD-1/PD-L1 axis has transformed the field of immune-oncology. 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 PD-L1 potently inhibits the type I interferon pathway in cancer cells. Hampered type I interferon responses in PD-L1-expressing cells resulted in enhanced infection with oncolytic viruses in cancer cells in vitro and in vivo. PD-L1 expression marks tumor explants from cancer patients that are best infected by oncolytic viruses. Agonistic antibodies targeting PD-L1 further reduced type I IFN responses and enhanced oncolytic virus infection. Mechanistically, PD-L1 suppressed type I interferon by promoting Warburg metabolism, characterized by enhanced glucose uptake and glycolysis rate. Lactate generated from glycolysis was the key metabolite responsible for inhibiting type I interferon responses and enhancing oncolytic virus infection in PD‑L1‑expressing cells. In addition to adding mechanistic insight into PD-L1 intrinsic function and showing that PD-L1 has a broader impact on immunity and cancer biology besides acting as a ligand for PD-1, our results will also help guide the numerous efforts currently ongoing to combine PD-L1 antibodies with oncolytic virotherapy in clinical trials.
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Overall design |
PolyA RNA-seq of wild-type and PD-L1-KO TRAMP2-C2 cells with and without infection with the oncolytic virus VSVdelta51-YFP at an MOI of 0.1 for 8 hours
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Contributor(s) |
Cook DP, Hodgins JJ, Ardolino M |
Citation missing |
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Submission date |
Aug 09, 2022 |
Last update date |
Jun 28, 2023 |
Contact name |
David Cook |
E-mail(s) |
David.cook@uottawa.ca
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Organization name |
Ottawa Hospital Research Institute
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Department |
Cancer Therapeutics Program
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Street address |
501 Smyth Rd
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City |
Ottawa |
State/province |
ON |
ZIP/Postal code |
K1H8L6 |
Country |
Canada |
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Platforms (1) |
GPL24247 |
Illumina NovaSeq 6000 (Mus musculus) |
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Samples (12)
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GSM6439697 |
PD-L1 wildtype TRAMP-C2 without oncolytic virus infection (rep 1) [Thy1_Mock_1] |
GSM6439698 |
PD-L1 wildtype TRAMP-C2 without oncolytic virus infection (rep 2) [Thy1_Mock_2] |
GSM6439699 |
PD-L1 wildtype TRAMP-C2 without oncolytic virus infection (rep 3) [Thy1_Mock_3] |
GSM6439700 |
PD-L1 wildtype TRAMP-C2 after 8hr of oncolytic virus infection (MOI 0.1; rep 1) [Thy1_MOI_01_1] |
GSM6439701 |
PD-L1 wildtype TRAMP-C2 after 8hr of oncolytic virus infection (MOI 0.1; rep 2) [Thy1_MOI_01_2] |
GSM6439702 |
PD-L1 wildtype TRAMP-C2 after 8hr of oncolytic virus infection (MOI 0.1; rep 3) [Thy1_MOI_01_3] |
GSM6439703 |
PD-L1 knockout TRAMP-C2 without oncolytic virus infection (rep 1) [PDL1_KO_Mock_1] |
GSM6439704 |
PD-L1 knockout TRAMP-C2 without oncolytic virus infection (rep 2) [PDL1_KO_Mock_2] |
GSM6439705 |
PD-L1 knockout TRAMP-C2 without oncolytic virus infection (rep 3) [PDL1_KO_Mock_3] |
GSM6439706 |
PD-L1 knockout TRAMP-C2 after 8hr of oncolytic virus infection (MOI 0.1; rep 1) [PDL1_KO_MOI_01_1] |
GSM6439707 |
PD-L1 knockout TRAMP-C2 after 8hr of oncolytic virus infection (MOI 0.1; rep 2) [PDL1_KO_MOI_01_2] |
GSM6439708 |
PD-L1 knockout TRAMP-C2 after 8hr of oncolytic virus infection (MOI 0.1; rep 3) [PDL1_KO_MOI_01_3] |
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Relations |
BioProject |
PRJNA868100 |