Low‐Dose Chemotherapy Preferentially Shapes the Ileal Microbiome and Augments the Response to Immune Checkpoint Blockade by Activating AIM2 Inflammasome in Ileal Epithelial Cells
| Title: | Low‐Dose Chemotherapy Preferentially Shapes the Ileal Microbiome and Augments the Response to Immune Checkpoint Blockade by Activating AIM2 Inflammasome in Ileal Epithelial Cells |
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| Authors: | Congying Pu, Yize Li, Yixian Fu, Yiyang Yan, Siyao Tao, Shuai Tang, Xiameng Gai, Ziyi Ding, Zhenjie Gan, Yingluo Liu, Siyuwei Cao, Ting Wang, Jian Ding, Jun Xu, Meiyu Geng, Min Huang |
| Source: | Advanced Science, Vol 11, Iss 11, Pp n/a-n/a (2024) |
| Publisher Information: | Wiley, 2024. |
| Publication Year: | 2024 |
| Collection: | LCC:Science |
| Subject Terms: | AIM2 inflammasome, chemotherapy, gut microbiome, ileal epithelial cells, immune checkpoint blockade, lactobacillus, Science |
| More Details: | Abstract 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. |
| Document Type: | article |
| File Description: | electronic resource |
| Language: | English |
| ISSN: | 2198-3844 20230478 |
| Relation: | https://doaj.org/toc/2198-3844 |
| DOI: | 10.1002/advs.202304781 |
| Access URL: | https://doaj.org/article/3b216d8657ec4b5ebcaf0e915308894b |
| Accession Number: | edsdoj.3b216d8657ec4b5ebcaf0e915308894b |
| Database: | Directory of Open Access Journals |
| ISSN: | 21983844 20230478 |
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| DOI: | 10.1002/advs.202304781 |
| Published in: | Advanced Science |
| Language: | English |