TREM2 缺乏可重编肠道巨噬细胞和微生物群,从而增强抗 PD-1 肿瘤免疫疗法

IF 17.6 1区 医学 Q1 IMMUNOLOGY
Blanda Di Luccia, Martina Molgora, Darya Khantakova, Natalia Jaeger, Hao-Wei Chang, Rafael S. Czepielewski, Beth A. Helmink, Emily J. Onufer, José L. Fachi, Bishan Bhattarai, Tihana Trsan, Patrick F. Rodrigues, JinChao Hou, Jennifer K. Bando, Cristiane Sécca da Silva, Marina Cella, Susan Gilfillan, Robert D. Schreiber, Jeffrey I. Gordon, Marco Colonna
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引用次数: 0

摘要

肠道微生物群和肿瘤相关巨噬细胞(TAMs)会影响肿瘤对抗程序性细胞死亡蛋白1(PD-1)免疫检查点阻断的反应。通过阻断或删除髓系细胞上的巨噬细胞触发受体2(TREM2)对TAM进行重编程可减轻肿瘤生长,而缺乏功能性TREM2可增强抗PD-1对肿瘤的清除作用。在这里,我们发现抗 PD-1 治疗与 TREM2 缺乏相结合会诱导小鼠肠道巨噬细胞产生促炎症程序,并同时扩大肠道微生物群中的小反刍球菌(Ruminococcus gnavus)。给野生型小鼠灌胃R.gnavus增强了抗PD-1介导的肿瘤消除效果,再现了TREM2缺失时的效果。促炎性肠道环境与产生 TNF 的 CD4 + T 细胞向肿瘤床的扩张、循环增加和迁移相吻合。因此,TREM2通过调节肠道免疫环境和微生物群来远程控制抗PD-1免疫检查点阻断,而R. gnavus正成为一种潜在的益生菌制剂,可提高对抗PD-1的反应性。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
TREM2 deficiency reprograms intestinal macrophages and microbiota to enhance anti–PD-1 tumor immunotherapy
The gut microbiota and tumor-associated macrophages (TAMs) affect tumor responses to anti–programmed cell death protein 1 (PD-1) immune checkpoint blockade. Reprogramming TAM by either blocking or deleting the macrophage receptor triggering receptor on myeloid cells 2 (TREM2) attenuates tumor growth, and lack of functional TREM2 enhances tumor elimination by anti–PD-1. Here, we found that anti–PD-1 treatment combined with TREM2 deficiency in mice induces proinflammatory programs in intestinal macrophages and a concomitant expansion of Ruminococcus gnavus in the gut microbiota. Gavage of wild-type mice with R. gnavus enhanced anti–PD-1–mediated tumor elimination, recapitulating the effect occurring in the absence of TREM2. A proinflammatory intestinal environment coincided with expansion, increased circulation, and migration of TNF-producing CD4+ T cells to the tumor bed. Thus, TREM2 remotely controls anti–PD-1 immune checkpoint blockade through modulation of the intestinal immune environment and microbiota, with R. gnavus emerging as a potential probiotic agent for increasing responsiveness to anti-PD-1.
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来源期刊
Science Immunology
Science Immunology Immunology and Microbiology-Immunology
CiteScore
32.90
自引率
2.00%
发文量
183
期刊介绍: Science Immunology is a peer-reviewed journal that publishes original research articles in the field of immunology. The journal encourages the submission of research findings from all areas of immunology, including studies on innate and adaptive immunity, immune cell development and differentiation, immunogenomics, systems immunology, structural immunology, antigen presentation, immunometabolism, and mucosal immunology. Additionally, the journal covers research on immune contributions to health and disease, such as host defense, inflammation, cancer immunology, autoimmunity, allergy, transplantation, and immunodeficiency. Science Immunology maintains the same high-quality standard as other journals in the Science family and aims to facilitate understanding of the immune system by showcasing innovative advances in immunology research from all organisms and model systems, including humans.
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