Sundar R, Gut. 2022 Jul;71(7):1277-1288. 

研究旨在胃癌中研究通过表观遗传学交替启动子的使用来调节肿瘤的免疫微环境，并将其发现扩展到其他胃肠道肿瘤中去

研究使用一种新的生物信息学算法（proActiv）对备用启动子负担（APB）进行量化，从短读RNA测序中推断启动子活性，并将样本分为APBhigh、APBint和APBlow三组。此外，研究人员还进行单细胞RNA测序来分析肿瘤内的免疫微环境。一个人源化小鼠癌症体内模型被用来探索肿瘤动力学、交替启动子使用和人类免疫系统之间的动态时间互动。随后，研究人员评估用免疫疗法治疗的多个胃肠道肿瘤队列，以确定APB与治疗结果之间的相关性

结果显示，APB高的胃癌肿瘤表示出T细胞的细胞溶解活性水平下降，并表现出免疫耗竭的特征。单细胞RNA测序分析证实APB高的肿瘤中有不同的免疫群体和较低的T细胞比例。使用带有活跃的人类免疫系统的 "人源化小鼠 "进行体内功能研究，研究人员还发现APB和肿瘤生长之间有明显的时间关系，APB高的肿瘤几乎没有人类T细胞浸润。此外，对免疫疗法治疗的消化道癌症患者的分析证实，APB高的肿瘤对免疫检查点的抑制有抵抗力。与APBlow相比，APBhigh胃癌的无进展生存期明显较差

ABSTRACT

Objectives Epigenomic alterations in cancer interact with the immune microenvironment to dictate tumour evolution and therapeutic response. We aimed to study the regulation of the tumour immune microenvironment through epigenetic alternate promoter use in gastric cancer and to expand our findings to other gastrointestinal tumours.

Design Alternate promoter burden (APB) was quantified using a novel bioinformatic algorithm (proActiv) to infer promoter activity from short_x0002_read RNA sequencing and samples categorised into APBhigh, APBint and APBlow. Single-cell RNA sequencing was performed to analyse the intratumour immune microenvironment. A humanised mouse cancer in vivo model was used to explore dynamic temporal interactions between tumour kinetics, alternate 

promoter usage and the human immune system. Multiple cohorts of gastrointestinal tumours treated with immunotherapy were assessed for correlation between APB and treatment outcomes.

Results APBhigh gastric cancer tumours expressed decreased levels of T-cell cytolytic activity and exhibited signatures of immune depletion. Single-cell RNAsequencing analysis confirmed distinct immunological populations and lower T_x0002_cell proportions in APBhigh tumours. Functional in vivo studies using ’humanised mice’harbouring an active human immune system revealed distinct temporal relationships between APB and tumour growth, with APBhigh tumours having almost no human T-cell infiltration. Analysis of immunotherapy-treated patients with GI cancer confirmed resistance of APB high tumours to immune checkpoint inhibition. APBhigh gastric cancer exhibited significantly poorer progression-free survival compared with APBlow (median 55 days vs 121 days, HR 0.40, 95% CI 0.18 to 0.93, p=0.032).

Conclusion These findings demonstrate an association between alternate promoter use and the tumour microenvironment, leading to immune evasion and immunotherapy resistance.

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