IDO1 inhibitors are synergistic with CXCL10 agonists in inhibiting colon cancer growth.
Biomed Pharmacother
; 179: 117412, 2024 Oct.
Article
en En
| MEDLINE
| ID: mdl-39255734
ABSTRACT
Indoleamine 2,3-dioxygenase 1 (IDO1) is an immune checkpoint that degrades L-tryptophan to kynurenine (Kyn) and enhance immunosuppression, which can be an attractive target for treating colon cancer. IDO1 inhibitors have limited efficacy when used as monotherapies, and their combination approach has been shown to provide synergistic benefits. Many studies have shown that targeting chemokines can promote the efficacy of immune checkpoint inhibitors. Therefore, this study explored the use of IDO1 inhibitors with multiple chemokines to develop a new combination regimen for IDO1 inhibitors. We found that IDO1 inhibitors reduce the secretion of C-X-C motif ligand 10(CXCL10) in cancer cells, and CXCL10 supplementation significantly improved the anticancer effect of IDO1 inhibitors. The combination of the IDO1 inhibitor with CXCL10 or its agonist axitinib had a synergistic inhibitory effect on the growth of colon cancer cells and transplanted CT26 tumors. This synergistic effect may be achieved by inhibiting cancer cell proliferation, promoting cancer cell apoptosis, promoting CD8+T cell differentiation and decreasing Tregs. Two downstream pathways of IDO1 affect CXCL10 secretion. One being the Kyn-aryl hydrocarbon receptor (AHR) pathway, the other is the general control nonderepressible 2(GCN2). Our study provides a new reference for combination regimens of IDO1 inhibitors.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Neoplasias del Colon
/
Proliferación Celular
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Sinergismo Farmacológico
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Indolamina-Pirrol 2,3,-Dioxigenasa
/
Quimiocina CXCL10
Límite:
Animals
/
Humans
Idioma:
En
Revista:
Biomed Pharmacother
Año:
2024
Tipo del documento:
Article
Pais de publicación:
Francia