FLI1 promotes IFN-γ-induced kynurenine production to impair anti-tumor immunity.
Nat Commun
; 15(1): 4590, 2024 May 30.
Article
en En
| MEDLINE
| ID: mdl-38816360
ABSTRACT
Nasopharyngeal carcinoma (NPC)-mediated immunosuppression within the tumor microenvironment (TME) frequently culminates in the failure of otherwise promising immunotherapies. In this study, we identify tumor-intrinsic FLI1 as a critical mediator in impairing T cell anti-tumor immunity. A mechanistic inquiry reveals that FLI1 orchestrates the expression of CBP and STAT1, facilitating chromatin accessibility and transcriptional activation of IDO1 in response to T cell-released IFN-γ. This regulatory cascade ultimately leads to augmented IDO1 expression, resulting in heightened synthesis of kynurenine (Kyn) in tumor cells. This, in turn, fosters CD8+ T cell exhaustion and regulatory T cell (Treg) differentiation. Intriguingly, we find that pharmacological inhibition of FLI1 effectively obstructs the CBP/STAT1-IDO1-Kyn axis, thereby invigorating both spontaneous and checkpoint therapy-induced immune responses, culminating in enhanced tumor eradication. In conclusion, our findings delineate FLI1-mediated Kyn metabolism as an immune evasion mechanism in NPC, furnishing valuable insights into potential therapeutic interventions.
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Interferón gamma
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Linfocitos T Reguladores
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Indolamina-Pirrol 2,3,-Dioxigenasa
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Factor de Transcripción STAT1
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Proteína Proto-Oncogénica c-fli-1
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Microambiente Tumoral
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Quinurenina
Idioma:
En
Revista:
Nat Commun
Asunto de la revista:
BIOLOGIA
/
CIENCIA
Año:
2024
Tipo del documento:
Article
País de afiliación:
China