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组织驻留巨噬细胞为早期NSCLC细胞提供了促肿瘤发生的微环境
2021-06-20 16:23

美国西奈山伊坎医学院Miriam Merad、María Casanova-Acebes等研究人员合作发现,组织驻留巨噬细胞为早期NSCLC细胞提供了促肿瘤发生的微环境。2021年6月16日,《自然》杂志在线发表这一研究成果。

为了探索人类非小细胞肺癌(NSCLC)病变中巨噬细胞区室的多样性,研究人员对肿瘤相关白细胞进行了单细胞RNA测序。研究人员确定了富含人和小鼠肺部肿瘤的不同巨噬细胞群。使用谱系追踪,研究人员发现这些巨噬细胞群的起源不同,并且在TME中具有明显的时空分布。在肿瘤形成早期,组织驻留巨噬细胞在靠近肿瘤细胞处积累,从而促进肿瘤细胞的上皮-间充质转化和侵袭性,它们还诱导有效的调节性T细胞反应,并保护肿瘤细胞免受适应性免疫的影响。

组织驻留巨噬细胞的消耗减少了调节性T细胞的数量并改变了表型,进而促进了CD8+T细胞的积累并降低了肿瘤的侵袭性和生长。在肿瘤生长过程中,组织驻留巨噬细胞在肿瘤微环境(TME)的外围重新分布;在小鼠和人类NSCLC中,TME的外围由单核细胞衍生的巨噬细胞主导。该研究确定了组织驻留巨噬细胞对早期肺癌的贡献,并将其作为预防和治疗早期肺癌病变的靶点。

据介绍,巨噬细胞在塑造TME、肿瘤免疫以及对免疫治疗的反应方面起着关键作用,这使它们成为癌症治疗的重要靶点。然而,事实证明调节巨噬细胞极其困难,因为人们仍然缺乏对肿瘤巨噬细胞区室的分子和功能多样性的完整了解。巨噬细胞来自两个不同的谱系。组织驻留巨噬细胞在局部自我更新,独立于成体造血,而短寿命的单核细胞衍生巨噬细胞来自成体造血干细胞,并且主要在发炎的病变中积累。这些巨噬细胞谱系如何促进TME和癌症进展尚不清楚。

附:英文原文

Title: Tissue-resident macrophages provide a pro-tumorigenic niche to early NSCLC cells

Author: Mara Casanova-Acebes, Erica Dalla, Andrew M. Leader, Jessica LeBerichel, Jovan Nikolic, Blanca M. Morales, Markus Brown, Christie Chang, Leanna Troncoso, Steven T. Chen, Ana Sastre-Perona, Matthew D. Park, Alexandra Tabachnikova, Maxime Dhainaut, Pauline Hamon, Barbara Maier, Catherine M. Sawai, Esperanza Agull-Pascual, Markus Schober, Brian D. Brown, Boris Reizis, Thomas Marron, Ephraim Kenigsberg, Christine Moussion, Philippe Benaroch, Julio A. Aguirre-Ghiso, Miriam Merad

Issue&Volume: 2021-06-16

Abstract: Macrophages have a key role in shaping the tumour microenvironment (TME), tumour immunity and response to immunotherapy, which makes them an important target for cancer treatment1,2. However, modulating macrophages has proved extremely difficult, as we still lack a complete understanding of the molecular and functional diversity of the tumour macrophage compartment. Macrophages arise from two distinct lineages. Tissue-resident macrophages self-renew locally, independent of adult haematopoiesis3,4,5, whereas short-lived monocyte-derived macrophages arise from adult haematopoietic stem cells, and accumulate mostly in inflamed lesions1. How these macrophage lineages contribute to the TME and cancer progression remains unclear. To explore the diversity of the macrophage compartment in human non-small cell lung carcinoma (NSCLC) lesions, here we performed single-cell RNA sequencing of tumour-associated leukocytes. We identified distinct populations of macrophages that were enriched in human and mouse lung tumours. Using lineage tracing, we discovered that these macrophage populations differ in origin and have a distinct temporal and spatial distribution in the TME. Tissue-resident macrophages accumulate close to tumour cells early during tumour formation to promote epithelial–mesenchymal transition and invasiveness in tumour cells, and they also induce a potent regulatory T cell response that protects tumour cells from adaptive immunity. Depletion of tissue-resident macrophages reduced the numbers and altered the phenotype of regulatory T cells, promoted the accumulation of CD8+ T cells and reduced tumour invasiveness and growth. During tumour growth, tissue-resident macrophages became redistributed at the periphery of the TME, which becomes dominated by monocyte-derived macrophages in both mouse and human NSCLC. This study identifies the contribution of tissue-resident macrophages to early lung cancer and establishes them as a target for the prevention and treatment of early lung cancer lesions.

DOI: 10.1038/s41586-021-03651-8

Source: https://www.nature.com/articles/s41586-021-03651-8

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:43.07
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html


本期文章:《自然》:Online/在线发表

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