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ALDOB/KAT2A相互作用在肝细胞致癌过程中表观遗传调节TGF-β表达和T细胞功能

Chunzhao Yin^1,2,3, Cunzhen Zhang⁴, Yongqiang Wang¹

¹CAS Key Laboratory of Nutrition, Metabolism and Food Safety Research, Shanghai Institute of Nutrition and Health (SINH), Chinese Academy of Sciences (CAS), Shanghai, China.

Hepatology (Baltimore, Md.)

|December 5, 2023

概括

肝癌细胞中果糖-1,6-二酸盐阿尔多酶B (ALDOB) 的降低通过表观遗传抑制TGF-β.促进瘤生长. 这种代谢重编程有助于癌细胞逃避免疫监测,并影响免疫治疗反应.

科学领域:

癌症新陈代谢癌症新陈代谢
免疫学免疫学免疫学
表观遗传学在表观遗传学中,表观遗传学是指表观遗传学.

背景情况:

瘤细胞与免疫细胞相互作用,逃避监测并影响免疫治疗结果.
肝细胞癌 (HCC) 细胞中果糖-1,6-双酸盐阿尔多酶B (ALDOB) 的下调促进瘤生长.
ALDOB表达对HCC瘤微环境的影响尚不清楚.

研究的目的:

研究ALDOB在瘤细胞中对瘤微环境和HCC中的免疫逃避作用.
阐明ALDOB影响HCC进展和免疫治疗反应的分子机制.

主要方法:

在人类HCC组织中分析ALDOB表达和CD8+T细胞透.
使用肝脏特异性ALDOB淘汰赛小鼠和ALDOB淘汰赛瘤模型的体内研究.
研究TGF-β信号通路,Treg细胞种群和CD8+T细胞活性.
机理研究涉及ALDOB的核定位,与氨酸转移酶2A的相互作用和H3K9乙化.
对结合TGF-β和PD-1阻断的治疗策略的评估.

主要成果:

在HCC中,ALDOB下调与减少CD8+T细胞透和耗尽相关.
瘤细胞中的ALDOB缺乏增加了TGF-β的表达,导致更多的Treg细胞和CD8+T细胞功能受损.
低的ALDOB和高的TGF-β表达预测了患者的生存率不佳.
结合阻断TGF-β和PD-1在小鼠中增加抑制了瘤生长.
ALDOB 与核中的 lysine acetyltransferase 2A 相互作用,通过 H3K9 乙化抑制 TGFB1 转录.

结论:

ALDOB在瘤细胞中表观遗传调节TGF-β信号传递,有助于HCC的免疫逃避.
这种代谢酶的核功能会影响瘤的微环境和免疫疗法的有效性.
准ALDOB或TGF-β信号可能代表HCC的新治疗策略.

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