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肺成纤维细胞通过重塑局部免疫微环境促进转移前微环境的形成
作者:小柯机器人 发布时间:2022/8/5 15:44:07

美国杰克逊实验室Guangwen Ren研究组发现,肺成纤维细胞通过重塑局部免疫微环境促进转移前微环境的形成。相关论文于2022年7月30日在线发表于国际学术期刊《免疫》。

通过单细胞RNA测序和免疫荧光,研究人员确定了一个表达环氧化酶2(COX-2)的肺前成纤维细胞群体重塑了肺部免疫微环境。在稳定状态下,肺部的成纤维细胞产生前列腺素E2(PGE2),从而驱动功能失调的树突状细胞(DC)和抑制性单核细胞。这种肺内基质程序被肿瘤相关的炎症,特别是促炎症细胞因子白细胞介素-1β所传播,从而支持了一个转移前的微环境。成纤维细胞中Ptgs2(编码COX-2)的基因敲除足以逆转驻肺骨髓细胞的免疫抑制表型,从而在多种乳腺癌模型中提高了免疫激活度并减少了肺转移。

此外,纤维细胞特异性Ptgs2缺失或PGE2受体EP2和EP4的双重抑制使基于DC的治疗和PD-1阻断的抗转移活性得到改善。总的来说,肺驻留的成纤维细胞重塑了局部的免疫环境,并促进了乳腺癌的转移。

据悉,原发性肿瘤是转移前微环境形成的驱动力,但二级器官对转移性传播的协调作用却没有得到重视。

附:英文原文

Title: Lung fibroblasts facilitate pre-metastatic niche formation by remodeling the local immune microenvironment

Author: Zheng Gong, Qing Li, Jiayuan Shi, Jian Wei, Peishan Li, Chih-Hao Chang, Leonard D. Shultz, Guangwen Ren

Issue&Volume: 2022-07-30

Abstract: Primary tumors are drivers of pre-metastatic niche formation, but the coordinationby the secondary organ toward metastatic dissemination is underappreciated. Here,by single-cell RNA sequencing and immunofluorescence, we identified a population ofcyclooxygenase 2 (COX-2)-expressing adventitial fibroblasts that remodeled the lungimmune microenvironment. At steady state, fibroblasts in the lungs produced prostaglandinE2 (PGE2), which drove dysfunctional dendritic cells (DCs) and suppressive monocytes.This lung-intrinsic stromal program was propagated by tumor-associated inflammation,particularly the pro-inflammatory cytokine interleukin-1β, supporting a pre-metastaticniche. Genetic ablation of Ptgs2 (encoding COX-2) in fibroblasts was sufficient to reverse the immune-suppressivephenotypes of lung-resident myeloid cells, resulting in heightened immune activationand diminished lung metastasis in multiple breast cancer models. Moreover, the anti-metastaticactivity of DC-based therapy and PD-1 blockade was improved by fibroblast-specificPtgs2 deletion or dual inhibition of PGE2 receptors EP2 and EP4. Collectively, lung-residentfibroblasts reshape the local immune landscape to facilitate breast cancer metastasis.

DOI: 10.1016/j.immuni.2022.07.001

Source: https://www.cell.com/immunity/fulltext/S1074-7613(22)00334-X

期刊信息

Immunity:《免疫》,创刊于1994年。隶属于细胞出版社,最新IF:21.522
官方网址:https://www.cell.com/immunity/home
投稿链接:https://www.editorialmanager.com/immunity/default.aspx