PD-L1 promotes oncolytic virus infection via a metabolic shift that inhibits the type I IFN pathway.
J Exp Med
; 221(7)2024 Jul 01.
Article
en En
| MEDLINE
| ID: mdl-38869480
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.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Interferón Tipo I
/
Virus Oncolíticos
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Viroterapia Oncolítica
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Antígeno B7-H1
Límite:
Animals
/
Female
/
Humans
/
Male
Idioma:
En
Revista:
J Exp Med
Año:
2024
Tipo del documento:
Article
País de afiliación:
Canadá