当前位置: X-MOL 学术Nature › 论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
In situ tumour arrays reveal early environmental control of cancer immunity
Nature ( IF 50.5 ) Pub Date : 2023-05-31 , DOI: 10.1038/s41586-023-06132-2
Guadalupe Ortiz-Muñoz 1 , Markus Brown 1 , Catherine B Carbone 1 , Ximo Pechuan-Jorge 1 , Vincent Rouilly 1 , Henrik Lindberg 1 , Alex T Ritter 1 , Gautham Raghupathi 2 , Qianbo Sun 1 , Tess Nicotra 1 , Shreya R Mantri 1 , Angela Yang 1 , Jonas Doerr 1 , Deepti Nagarkar 1 , Spyros Darmanis 1 , Benjamin Haley 1 , Sanjeev Mariathasan 1 , Yulei Wang 1 , Carlos Gomez-Roca 3 , Carlos Eduardo de Andrea 4 , David Spigel 5 , Thomas Wu 1 , Lelia Delamarre 1 , Johannes Schöneberg 6, 7 , Zora Modrusan 1 , Richard Price 1 , Shannon J Turley 1 , Ira Mellman 1 , Christine Moussion 1
Affiliation  

The immune phenotype of a tumour is a key predictor of its response to immunotherapy1,2,3,4. Patients who respond to checkpoint blockade generally present with immune-inflamed5,6,7 tumours that are highly infiltrated by T cells. However, not all inflamed tumours respond to therapy, and even lower response rates occur among tumours that lack T cells (immune desert) or that spatially exclude T cells to the periphery of the tumour lesion (immune excluded)8. Despite the importance of these tumour immune phenotypes in patients, little is known about their development, heterogeneity or dynamics owing to the technical difficulty of tracking these features in situ. Here we introduce skin tumour array by microporation (STAMP)—a preclinical approach that combines high-throughput time-lapse imaging with next-generation sequencing of tumour arrays. Using STAMP, we followed the development of thousands of arrayed tumours in vivo to show that tumour immune phenotypes and outcomes vary between adjacent tumours and are controlled by local factors within the tumour microenvironment. Particularly, the recruitment of T cells by fibroblasts and monocytes into the tumour core was supportive of T cell cytotoxic activity and tumour rejection. Tumour immune phenotypes were dynamic over time and an early conversion to an immune-inflamed phenotype was predictive of spontaneous or therapy-induced tumour rejection. Thus, STAMP captures the dynamic relationships of the spatial, cellular and molecular components of tumour rejection and has the potential to translate therapeutic concepts into successful clinical strategies.



中文翻译:

原位肿瘤阵列揭示了癌症免疫的早期环境控制

肿瘤的免疫表型是其对免疫治疗反应的关键预测因素1,2,3,4。对检查点封锁有反应的患者通常会出现免疫发炎的5、6、7肿瘤,这些肿瘤被 T 细胞高度浸润。然而,并非所有发炎的肿瘤都对治疗有反应,在缺乏 T 细胞(免疫沙漠)或在空间上将 T 细胞排除在肿瘤病灶周围(免疫排除)的肿瘤中,反应率甚至更低8。尽管这些肿瘤免疫表型对患者很重要,但由于原位追踪这些特征的技术困难,人们对它们的发展、异质性或动态知之甚少。在这里,我们介绍微孔化皮肤肿瘤阵列(STAMP)——一种将高通量延时成像与下一代肿瘤阵列测序相结合的临床前方法。使用 STAMP,我们跟踪了体内数千个阵列肿瘤的发育,结果表明肿瘤免疫表型和结果在相邻肿瘤之间存在差异,并受肿瘤微环境中的局部因素控制。特别是,成纤维细胞和单核细胞将 T 细胞募集到肿瘤核心,支持 T 细胞的细胞毒活性和肿瘤排斥。肿瘤免疫表型随着时间的推移呈动态变化,早期转化为免疫炎症表型可预测自发性或治疗诱导的肿瘤排斥。因此,STAMP 捕捉了肿瘤排斥的空间、细胞和分子成分的动态关系,并有可能将治疗概念转化为成功的临床策略。

更新日期:2023-06-01
down
wechat
bug