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Low-Dose Chemotherapy Preferentially Shapes the Ileal Microbiome and Augments the Response to Immune Checkpoint Blockade by Activating AIM2 Inflammasome in Ileal Epithelial Cells

文献类型：期刊论文

作者Pu, Congying2,3; Li, Yize2,3; Fu, Yixian1,3; Yan, Yiyang2,3; Tao, Siyao2,3; Tang, Shuai3,4; Gai, Xiameng1,3; Ding, Ziyi2,3; Gan, Zhenjie2,3; Liu, Yingluo2,3
刊名ADVANCED SCIENCE
出版日期2024-01-08
页码17
关键词AIM2 inflammasome chemotherapy gut microbiome ileal epithelial cells immune checkpoint blockade lactobacillus segmented filamentous bacterium
DOI10.1002/advs.202304781
通讯作者Xu, Jun(jxu@simm.ac.cn) ; Geng, Meiyu(mygeng@simm.ac.cn) ; Huang, Min(mhuang@simm.ac.cn)
英文摘要Intervention of the gut microbiome is a promising adjuvant strategy in cancer immunotherapy. Chemotherapeutic agents are recognized for their substantial impacts on the gut microbiome, yet their therapeutic potential as microbiome modulators remains uncertain, due to the complexity of microbiome-host-drug interactions. Here, it is showed that low-dose chemotherapy preferentially shapes the ileal microbiome to augment the extraintestinal immune response to anti-programmed death-1 (anti-PD-1) therapy without causing intestinal toxicity. Mechanistically, low-dose chemotherapy causes DNA damage restricted to highly-proliferative ileal epithelial cells, resulting in the accumulation of cytosolic dsDNA and the activation of the absent in melanoma 2 (AIM2) inflammasome. AIM2-dependent IL-18 secretion triggers the interplay between proximal Th1 cells and Paneth cells in ileal crypts, impairing the local antimicrobial host defense and resulting in ileal microbiome change. Intestinal epithelium-specific knockout of AIM2 in mice significantly attenuates CPT-11-caused IL-18 secretion, Paneth cell dysfunction, and ileal microbiome alteration. Moreover, AIM2 deficiency in mice or antibiotic microbial depletion attenuates chemotherapy-augmented antitumor responses to anti-PD1 therapy. Collectively, these findings provide mechanistic insights into how chemotherapy-induced genomic stress is transduced to gut microbiome change and support the rationale of applying low-dose chemotherapy as a promising adjuvant strategy in cancer immunotherapy with minimal toxicity. Low-dose chemotherapy causes DNA damage restricted to highly-proliferative ileal epithelial cells without causing intestinal toxicity, resulting in the activation of the absent in melanoma 2 (AIM2) inflammasome. AIM2-dependent IL-18 secretion triggers the interplay between proximal Th1 cells and Paneth cells in ileal crypts, shaping the ileal microbiome pattern and augmenting antitumor responses to anti-PD1 therapy.image
WOS关键词PANETH CELLS ; FECAL MICROBIOTA ; DNA ; EFFICACY ; DIFFERENTIATION ; MUCOSITIS ; SEQUENCES ; CYTOKINES ; BACTERIA ; GROWTH
资助项目Chinese Academy of Sciences[22337004] ; Chinese Academy of Sciences[82225046] ; Chinese Academy of Sciences[81821005] ; Chinese Academy of Sciences[81903640] ; National Natural Science Foundation of China[YDZX20233100004032] ; National Natural Science Foundation of China[20XD1424800] ; Science and Technology Commission of Shanghai Municipality[XDA12020102] ; Strategic Priority Research Program of the Chinese Academy of Sciences
WOS研究方向Chemistry ; Science & Technology - Other Topics ; Materials Science
语种英语
WOS记录号WOS:001142097500001
出版者WILEY
源URL[http://119.78.100.183/handle/2S10ELR8/308766]  
专题新药研究国家重点实验室
通讯作者Xu, Jun; Geng, Meiyu; Huang, Min
作者单位1.Nanchang Univ, Jiangxi Med Coll, Sch Pharm, Nanchang 330031, Peoples R China
2.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
3.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China
4.Bohai Rim Adv Res Inst Drug Discovery, Shandong Lab Yantai Drug Discovery, Yantai 264117, Peoples R China
推荐引用方式
GB/T 7714		 Pu, Congying,Li, Yize,Fu, Yixian,et al. Low-Dose Chemotherapy Preferentially Shapes the Ileal Microbiome and Augments the Response to Immune Checkpoint Blockade by Activating AIM2 Inflammasome in Ileal Epithelial Cells[J]. ADVANCED SCIENCE,2024:17.
APA Pu, Congying.,Li, Yize.,Fu, Yixian.,Yan, Yiyang.,Tao, Siyao.,...&Huang, Min.(2024).Low-Dose Chemotherapy Preferentially Shapes the Ileal Microbiome and Augments the Response to Immune Checkpoint Blockade by Activating AIM2 Inflammasome in Ileal Epithelial Cells.ADVANCED SCIENCE,17.
MLA Pu, Congying,et al."Low-Dose Chemotherapy Preferentially Shapes the Ileal Microbiome and Augments the Response to Immune Checkpoint Blockade by Activating AIM2 Inflammasome in Ileal Epithelial Cells".ADVANCED SCIENCE (2024):17.

入库方式： OAI收割

来源：上海药物研究所

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