小柯机器人

切换到桌面版
研究揭示检查点阻断依赖性抗肿瘤免疫中POLE和POLD1突变的功能图谱
2022-07-14 15:06
来源：小柯机器人

近日，美国克利夫兰诊所Timothy A. Chan团队揭示检查点阻断依赖性抗肿瘤免疫中POLE和POLD1突变的功能图谱。这一研究成果于2022年7月11日在线发表在国际学术期刊《自然—遗传学》上。

研究人员全面地确定了POLE/POLD1突变在免疫检查点阻断疗法（ICB）中的影响，并阐明了这些突变对肿瘤免疫的机制影响。携带Pole/Pold1功能突变的小鼠同种异体肿瘤显示出增强的抗肿瘤免疫力，并对ICB敏感。携带明显突变特征的POLE/POLD1突变肿瘤的患者对ICB的反应比携带野生型或特征阴性肿瘤的患者好。一个基于POLE/D1功能相关特征的突变模型在识别受益于ICB的POLE/POLD1突变患者方面优于几种传统方法。
 
令人震惊的是，突变特征的谱系与新抗原的生化特征相关。导致POLE/POLD1功能相关特征的改变产生了与T细胞受体（TCR）接触的残基，其疏水性增加，可能有利于T细胞识别。总的来说，POLE/POLD1突变的功能图谱决定了免疫疗法的疗效。
 
据介绍，管理基因组保真度的途径的缺陷与ICB的反应改善有关。致病性的POLE/POLD1突变可引起高突变，然而POLE/POLD1的各种突变如何影响ICB后的抗肿瘤免疫力还不清楚。
 
附：英文原文
 
Title: Functional landscapes of POLE and POLD1 mutations in checkpoint blockade-dependent antitumor immunity

Author: Ma, Xiaoxiao, Riaz, Nadeem, Samstein, Robert M., Lee, Mark, Makarov, Vladimir, Valero, Cristina, Chowell, Diego, Kuo, Fengshen, Hoen, Douglas, Fitzgerald, Conall W. R., Jiang, Hui, Alektiar, Jonathan, Alban, Tyler J., Juric, Ivan, Parthasarathy, Prerana Bangalore, Zhao, Yu, Sabio, Erich Y., Verma, Richa, Srivastava, Raghvendra M., Vuong, Lynda, Yang, Wei, Zhang, Xiao, Wang, Jingming, Chu, Lawrence K., Wang, Stephen L., Kelly, Daniel W., Pei, Xin, Chen, Jiapeng, Yaeger, Rona, Zamarin, Dmitriy, Zehir, Ahmet, Gnen, Mithat, Morris, Luc G. T., Chan, Timothy A.

Issue&Volume: 2022-07-11

Abstract: Defects in pathways governing genomic fidelity have been linked to improved response to immune checkpoint blockade therapy (ICB). Pathogenic POLE/POLD1 mutations can cause hypermutation, yet how diverse mutations in POLE/POLD1 influence antitumor immunity following ICB is unclear. Here, we comprehensively determined the effect of POLE/POLD1 mutations in ICB and elucidated the mechanistic impact of these mutations on tumor immunity. Murine syngeneic tumors harboring Pole/Pold1 functional mutations displayed enhanced antitumor immunity and were sensitive to ICB. Patients with POLE/POLD1 mutated tumors harboring telltale mutational signatures respond better to ICB than patients harboring wild-type or signature-negative tumors. A mutant POLE/D1 function-associated signature-based model outperformed several traditional approaches for identifying POLE/POLD1 mutated patients that benefit from ICB. Strikingly, the spectrum of mutational signatures correlates with the biochemical features of neoantigens. Alterations that cause POLE/POLD1 function-associated signatures generate T cell receptor (TCR)-contact residues with increased hydrophobicity, potentially facilitating T cell recognition. Altogether, the functional landscapes of POLE/POLD1 mutations shape immunotherapy efficacy.

DOI: 10.1038/s41588-022-01108-w

Source: https://www.nature.com/articles/s41588-022-01108-w

Nature Genetics：《自然—遗传学》，创刊于1992年。隶属于施普林格·自然出版集团，最新IF：41.307
官方网址：https://www.nature.com/ng/
投稿链接：https://mts-ng.nature.com/cgi-bin/main.plex


本期文章：《自然—遗传学》：Online/在线发表

分享到:

0