Nilotinib boosts the efficacy of anti-PDL1 therapy in colorectal cancer by restoring the expression of MHC-I.
J Transl Med
; 22(1): 769, 2024 Aug 14.
Article
en En
| MEDLINE
| ID: mdl-39143573
ABSTRACT
BACKGROUND:
Although immune checkpoint inhibitors (ICIs) have revolutionized the landscape of cancer treatment, only a minority of colorectal cancer (CRC) patients respond to them. Enhancing tumor immunogenicity by increasing major histocompatibility complex I (MHC-I) surface expression is a promising strategy to boost the antitumor efficacy of ICIs.METHODS:
Dual luciferase reporter assays were performed to find drug candidates that can increase MHC-I expression. The effect of nilotinib on MHC-I expression was verified by dual luciferase reporter assays, qRT-PCR, flow cytometry and western blotting. The biological functions of nilotinib were evaluated through a series of in vitro and in vivo experiments. Using RNA-seq analysis, immunofluorescence assays, western blotting, flow cytometry, rescue experiments and microarray chip assays, the underlying molecular mechanisms were investigated.RESULTS:
Nilotinib induces MHC-I expression in CRC cells, enhances CD8+ T-cell cytotoxicity and subsequently enhances the antitumor effects of anti-PDL1 in both microsatellite instability and microsatellite stable models. Mechanistically, nilotinib promotes MHC-I mRNA expression via the cGAS-STING-NF-κB pathway and reduces MHC-I degradation by suppressing PCSK9 expression in CRC cells. PCSK9 may serve as a potential therapeutic target for CRC, with nilotinib potentially targeting PCSK9 to exert anti-CRC effects.CONCLUSION:
This study reveals a previously unknown role of nilotinib in antitumor immunity by inducing MHC-I expression in CRC cells. Our findings suggest that combining nilotinib with anti-PDL1 therapy may be an effective strategy for the treatment of CRC.Palabras clave
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Bases de datos:
MEDLINE
Asunto principal:
Pirimidinas
/
Neoplasias Colorrectales
Límite:
Animals
/
Humans
Idioma:
En
Revista:
J Transl Med
Año:
2024
Tipo del documento:
Article
País de afiliación:
China