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由于影响瘤免疫微环境,CHEK2缺乏会增加对PD-1抑制剂的反应

Pingping Xu¹, Yaqi Gao¹, Shanshan Jiang¹

¹Division of Gastroenterology and Hepatology, Shanghai Institute of Digestive Disease, NHC Key Laboratory of Digestive Diseases, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

|December 14, 2023

概括

检查点激酶2 (CHEK2) 的缺陷突变增加了瘤突变负担,并通过调节瘤免疫微环境来增强免疫检查点阻塞 (ICB) 治疗的抗瘤效应,特别是抗PD-1.

科学领域:

在瘤学瘤学.
癌症免疫学癌症免疫学
遗传学是一个遗传学.

背景情况:

免疫检查点阻塞 (ICB) 疗法在癌症治疗中表现有前途.
像CHEK2和POLE中的DNA损伤修复 (DDR) 途径基因突变,可以影响基因组不稳定性和ICB疗效.

研究的目的:

研究CHEK2缺陷突变对ICB治疗反应的影响.

主要方法:

对胰腺癌数据库的分析,以比较具有和没有CHEK2突变的瘤的瘤突变负担 (TMB).
在体内研究中,使用使用抗PD-1疗法治疗的MC38和B16瘤携带小鼠.
瘤体积,体重和免疫细胞透 (CD8+ T细胞) 的评估.
检查瘤的免疫微环境和基因表达途径.
与携带POLE突变的小鼠模型进行比较.

主要成果:

CHEK2突变瘤的TMB显著高于CHEK2-WT瘤.
CHEK2缺陷突变增强了抗PD-1疗法的抗瘤作用,减少了瘤体积和体重.
CHEK2缺乏导致细胞毒性CD8+T细胞透增加,并调节瘤免疫微环境,调节免疫炎症和抗原呈现途径.
具有POLE突变的小鼠模型显示出与CHEK2缺陷模型在抗PD-1治疗后类似的突变和免疫景观.

结论:

CHEK2缺陷突变可能通过影响瘤免疫微环境来改善对抗PD-1等ICB疗法的反应.
CHEK2缺陷突变代表了免疫治疗反应的潜在预测生物标志物.
缺少CHEK2可以增强癌症免疫治疗的疗效.

关键词:

CHEK2 是一个国家.免疫系统的炎症途径.免疫治疗是一种免疫疗法.波兰波兰波兰瘤的免疫微环境

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