Low‐Dose Chemotherapy Preferentially Shapes the Ileal Microbiome and Augments the Response to Immune Checkpoint Blockade by Activating AIM2 Inflammasome in Ileal Epithelial Cells
-
Published:2024-01-08
Issue:
Volume:
Page:
-
ISSN:2198-3844
-
Container-title:Advanced Science
-
language:en
-
Short-container-title:Advanced Science
Author:
Pu Congying12,
Li Yize12,
Fu Yixian13,
Yan Yiyang12,
Tao Siyao12,
Tang Shuai14,
Gai Xiameng13,
Ding Ziyi12,
Gan Zhenjie12,
Liu Yingluo12,
Cao Siyuwei1,
Wang Ting12,
Ding Jian1234,
Xu Jun12,
Geng Meiyu124,
Huang Min124ORCID
Affiliation:
1. State Key Laboratory of Drug Research Shanghai Institute of Materia Medica Chinese Academy of Sciences Shanghai 201203 China
2. University of Chinese Academy of Sciences Beijing 100049 China
3. School of Pharmacy, Jiangxi Medical College Nanchang University Nanchang 330031 China
4. Shandong Laboratory of Yantai Drug Discovery Bohai Rim Advanced Research Institute for Drug Discovery Yantai 264117 China
Abstract
AbstractIntervention 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.
Funder
Chinese Academy of Sciences
Science and Technology Commission of Shanghai Municipality
National Natural Science Foundation of China
Subject
General Physics and Astronomy,General Engineering,Biochemistry, Genetics and Molecular Biology (miscellaneous),General Materials Science,General Chemical Engineering,Medicine (miscellaneous)