Kynurenine promotes the immune escape of colorectal cancer cells via NAT10-mediated ac4C acetylation of PD-L1

IF 2.2 4区医学 Q2 MEDICINE, GENERAL & INTERNAL

Clinics Pub Date : 2025-01-01 DOI:10.1016/j.clinsp.2025.100658

Zaibiao Wang , Manman Yin , Ruhang Zhou , Ming Li , Jie Peng , Zhengguang Wang

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引用次数: 0

Abstract

Background

This study aimed to investigate the role of kynurenine in Colorectal Cancer (CRC) and the underlying mechanism.

Methods

Enzyme-linked immunosorbent assay was employed to assess the kynurenine concentration. Flow cytometry was utilized to analyze the percentages of CD3+CD4+ and CD3+CD8+ T-cells. Immunofluorescence was used to measure the expression of Programmed Death-Ligand 1 (PD-L1). RNA modification levels in CRC cells were analyzed using a dot blot assay. The interaction between NAT10 and PD-L1 was assessed via RNA immunoprecipitation, dual-luciferase reporter, and immunofluorescence assays. A xenograft tumor rat model was established.

Results

Results indicated that kynurenine suppressed T-cell activation and promoted immune escape. Besides, kynurenine promoted N-Acetyltransferase 10 (NAT10)-mediated N4-acetylcytidine (ac⁴C) modification. Moreover, NAT10 inhibition improved T-cell activation and suppressed immune escape. Mechanically, NAT10 is bound with the mRNA of PD-L1. Rescue experiments showed that PD-L1 inhibitor treatment reversed the suppressed T-cell activation and the promoted immune escape induced by NAT10 overexpression. In vivo, studies indicated that NAT10 deficiency reversed the promoted tumor growth induced by kynurenine treatment.

Conclusion

In conclusion, kynurenine promoted the immune escape of CRC cells via NAT10-mediated ac⁴C acetylation of PD-L1.

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来源期刊

Clinics 医学-医学：内科

CiteScore

4.10

自引率

3.70%

发文量

129

审稿时长

52 days

期刊介绍： CLINICS is an electronic journal that publishes peer-reviewed articles in continuous flow, of interest to clinicians and researchers in the medical sciences. CLINICS complies with the policies of funding agencies which request or require deposition of the published articles that they fund into publicly available databases. CLINICS supports the position of the International Committee of Medical Journal Editors (ICMJE) on trial registration.