Correction of arginine metabolism with sepiapterin-the precursor of nitric oxide synthase cofactor BH4-induces immunostimulatory-shift of breast cancer.
Biochem Pharmacol
; 176: 113887, 2020 06.
Article
en En
| MEDLINE
| ID: mdl-32112882
ABSTRACT
Immunotherapy is a first-line treatment for many tumor types. However, most breast tumors are immuno-suppressive and only modestly respond to immunotherapy. We hypothesized that correcting arginine metabolism might improve the immunogenicity of breast tumors. We tested whether supplementing sepiapterin, the precursor of tetrahydrobiopterin (BH4)-the nitric oxide synthase (NOS) cofactor-redirects arginine metabolism from the pathway synthesizing polyamines to that of synthesizing nitric oxide (NO) and make breast tumors more immunogenic. We showed that sepiapterin elevated NO but lowered polyamine levels in tumor cells, as well as in tumor-associated macrophages (TAMs). This not only suppressed tumor cell proliferation, but also induced the conversion of TAMs from the immuno-suppressive M2-type to immuno-stimulatory M1-type. Furthermore, sepiapterin abrogated the expression of a checkpoint ligand, PD-L1, in tumors in a STAT3-dependent manner. This is the first study which reveals that supplementing sepiapterin normalizes arginine metabolism, improves the immunogenicity and inhibits the growth of breast tumor cells.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Arginina
/
Poliaminas
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Pterinas
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Neoplasias de la Mama
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Macrófagos
/
Óxido Nítrico
Límite:
Humans
Idioma:
En
Revista:
Biochem Pharmacol
Año:
2020
Tipo del documento:
Article
País de afiliación:
Estados Unidos