Cargando…
Methylglyoxal from gut microbes boosts radiosensitivity and radioimmunotherapy in rectal cancer by triggering endoplasmic reticulum stress and cGAS-STING activation
BACKGROUND: Preoperative radiation therapy (preRT) is a fundamental aspect of neoadjuvant treatment for rectal cancer (RC), but the response to this treatment remains unsatisfactory. The combination of radiation therapy (RT) and immunotherapy (iRT) presents a promising approach to cancer treatment,...
Autores principales: | , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BMJ Publishing Group
2023
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10689421/ https://www.ncbi.nlm.nih.gov/pubmed/38035726 http://dx.doi.org/10.1136/jitc-2023-007840 |
_version_ | 1785152363231707136 |
---|---|
author | Zhou, Han Wang, Lei Lin, Zhiwen Jiang, Chenwei Chen, Xingte Wang, Kai Liu, Libin Shao, Lingdong Pan, Jianji Li, Jinluan Zhang, Da Wu, Junxin |
author_facet | Zhou, Han Wang, Lei Lin, Zhiwen Jiang, Chenwei Chen, Xingte Wang, Kai Liu, Libin Shao, Lingdong Pan, Jianji Li, Jinluan Zhang, Da Wu, Junxin |
author_sort | Zhou, Han |
collection | PubMed |
description | BACKGROUND: Preoperative radiation therapy (preRT) is a fundamental aspect of neoadjuvant treatment for rectal cancer (RC), but the response to this treatment remains unsatisfactory. The combination of radiation therapy (RT) and immunotherapy (iRT) presents a promising approach to cancer treatment, though the underlying mechanisms are not yet fully understood. The gut microbiota may influence the response to RT and immunotherapy. Therefore, we aimed to identify the metabolism of gut microbiota to reverse radioresistance and enhance the efficacy of iRT. METHODS: Fecal and serum samples were prospectively collected from patients with locally advanced rectal cancer (LARC) who had undergone pre-RT treatment. Candidate gut microbiome-derived metabolites linked with radiosensitization were screened using 16s rRNA gene sequencing and ultrahigh-performance liquid chromatography-mass coupled with mass spectrometry. In vitro and in vivo studies were conducted to assess the radiosensitizing effects of the metabolites including the syngeneic CT26 tumor model and HCT116 xenograft tumor model, transcriptomics and immunofluorescence. The CT26 abscopal effect modeling was employed to evaluate the combined effects of metabolites on iRT. RESULTS: We initially discovered the gut microbiota-associated metabolite, methylglyoxal (MG), which accurately predicts the response to preRT (Area Under Curve (AUC) value of 0.856) among patients with LARC. Subsequently, we observed that MG amplifies the RT response in RC by stimulating intracellular reactive oxygen species (ROS) and reducing hypoxia in the tumor in vitro and in vivo. Additionally, our study demonstrated that MG amplifies the RT-induced activation of the cyclic guanosine monophosphate AMP synthase-stimulator of interferon genes pathway by elevating DNA double-strand breaks. Moreover, it facilitates immunogenic cell death generated by ROS-mediated endoplasmic reticulum stress, consequently leading to an increase in CD8(+) T and natural killer cells infiltrated in the tumor immune microenvironment. Lastly, we discovered that the combination of anti-programmed cell death protein 1 (anti-PD1) therapy produced long-lasting complete responses in all irradiated tumor sites and half of the non-irradiated ones. CONCLUSIONS: Our research indicates that MG shows promise as a radiosensitizer and immunomodulator for RC. Furthermore, we propose that combining MG with iRT has great potential for clinical practice. |
format | Online Article Text |
id | pubmed-10689421 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | BMJ Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-106894212023-12-02 Methylglyoxal from gut microbes boosts radiosensitivity and radioimmunotherapy in rectal cancer by triggering endoplasmic reticulum stress and cGAS-STING activation Zhou, Han Wang, Lei Lin, Zhiwen Jiang, Chenwei Chen, Xingte Wang, Kai Liu, Libin Shao, Lingdong Pan, Jianji Li, Jinluan Zhang, Da Wu, Junxin J Immunother Cancer Clinical/Translational Cancer Immunotherapy BACKGROUND: Preoperative radiation therapy (preRT) is a fundamental aspect of neoadjuvant treatment for rectal cancer (RC), but the response to this treatment remains unsatisfactory. The combination of radiation therapy (RT) and immunotherapy (iRT) presents a promising approach to cancer treatment, though the underlying mechanisms are not yet fully understood. The gut microbiota may influence the response to RT and immunotherapy. Therefore, we aimed to identify the metabolism of gut microbiota to reverse radioresistance and enhance the efficacy of iRT. METHODS: Fecal and serum samples were prospectively collected from patients with locally advanced rectal cancer (LARC) who had undergone pre-RT treatment. Candidate gut microbiome-derived metabolites linked with radiosensitization were screened using 16s rRNA gene sequencing and ultrahigh-performance liquid chromatography-mass coupled with mass spectrometry. In vitro and in vivo studies were conducted to assess the radiosensitizing effects of the metabolites including the syngeneic CT26 tumor model and HCT116 xenograft tumor model, transcriptomics and immunofluorescence. The CT26 abscopal effect modeling was employed to evaluate the combined effects of metabolites on iRT. RESULTS: We initially discovered the gut microbiota-associated metabolite, methylglyoxal (MG), which accurately predicts the response to preRT (Area Under Curve (AUC) value of 0.856) among patients with LARC. Subsequently, we observed that MG amplifies the RT response in RC by stimulating intracellular reactive oxygen species (ROS) and reducing hypoxia in the tumor in vitro and in vivo. Additionally, our study demonstrated that MG amplifies the RT-induced activation of the cyclic guanosine monophosphate AMP synthase-stimulator of interferon genes pathway by elevating DNA double-strand breaks. Moreover, it facilitates immunogenic cell death generated by ROS-mediated endoplasmic reticulum stress, consequently leading to an increase in CD8(+) T and natural killer cells infiltrated in the tumor immune microenvironment. Lastly, we discovered that the combination of anti-programmed cell death protein 1 (anti-PD1) therapy produced long-lasting complete responses in all irradiated tumor sites and half of the non-irradiated ones. CONCLUSIONS: Our research indicates that MG shows promise as a radiosensitizer and immunomodulator for RC. Furthermore, we propose that combining MG with iRT has great potential for clinical practice. BMJ Publishing Group 2023-11-30 /pmc/articles/PMC10689421/ /pubmed/38035726 http://dx.doi.org/10.1136/jitc-2023-007840 Text en © Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. https://creativecommons.org/licenses/by-nc/4.0/This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See http://creativecommons.org/licenses/by-nc/4.0/ (https://creativecommons.org/licenses/by-nc/4.0/) . |
spellingShingle | Clinical/Translational Cancer Immunotherapy Zhou, Han Wang, Lei Lin, Zhiwen Jiang, Chenwei Chen, Xingte Wang, Kai Liu, Libin Shao, Lingdong Pan, Jianji Li, Jinluan Zhang, Da Wu, Junxin Methylglyoxal from gut microbes boosts radiosensitivity and radioimmunotherapy in rectal cancer by triggering endoplasmic reticulum stress and cGAS-STING activation |
title | Methylglyoxal from gut microbes boosts radiosensitivity and radioimmunotherapy in rectal cancer by triggering endoplasmic reticulum stress and cGAS-STING activation |
title_full | Methylglyoxal from gut microbes boosts radiosensitivity and radioimmunotherapy in rectal cancer by triggering endoplasmic reticulum stress and cGAS-STING activation |
title_fullStr | Methylglyoxal from gut microbes boosts radiosensitivity and radioimmunotherapy in rectal cancer by triggering endoplasmic reticulum stress and cGAS-STING activation |
title_full_unstemmed | Methylglyoxal from gut microbes boosts radiosensitivity and radioimmunotherapy in rectal cancer by triggering endoplasmic reticulum stress and cGAS-STING activation |
title_short | Methylglyoxal from gut microbes boosts radiosensitivity and radioimmunotherapy in rectal cancer by triggering endoplasmic reticulum stress and cGAS-STING activation |
title_sort | methylglyoxal from gut microbes boosts radiosensitivity and radioimmunotherapy in rectal cancer by triggering endoplasmic reticulum stress and cgas-sting activation |
topic | Clinical/Translational Cancer Immunotherapy |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10689421/ https://www.ncbi.nlm.nih.gov/pubmed/38035726 http://dx.doi.org/10.1136/jitc-2023-007840 |
work_keys_str_mv | AT zhouhan methylglyoxalfromgutmicrobesboostsradiosensitivityandradioimmunotherapyinrectalcancerbytriggeringendoplasmicreticulumstressandcgasstingactivation AT wanglei methylglyoxalfromgutmicrobesboostsradiosensitivityandradioimmunotherapyinrectalcancerbytriggeringendoplasmicreticulumstressandcgasstingactivation AT linzhiwen methylglyoxalfromgutmicrobesboostsradiosensitivityandradioimmunotherapyinrectalcancerbytriggeringendoplasmicreticulumstressandcgasstingactivation AT jiangchenwei methylglyoxalfromgutmicrobesboostsradiosensitivityandradioimmunotherapyinrectalcancerbytriggeringendoplasmicreticulumstressandcgasstingactivation AT chenxingte methylglyoxalfromgutmicrobesboostsradiosensitivityandradioimmunotherapyinrectalcancerbytriggeringendoplasmicreticulumstressandcgasstingactivation AT wangkai methylglyoxalfromgutmicrobesboostsradiosensitivityandradioimmunotherapyinrectalcancerbytriggeringendoplasmicreticulumstressandcgasstingactivation AT liulibin methylglyoxalfromgutmicrobesboostsradiosensitivityandradioimmunotherapyinrectalcancerbytriggeringendoplasmicreticulumstressandcgasstingactivation AT shaolingdong methylglyoxalfromgutmicrobesboostsradiosensitivityandradioimmunotherapyinrectalcancerbytriggeringendoplasmicreticulumstressandcgasstingactivation AT panjianji methylglyoxalfromgutmicrobesboostsradiosensitivityandradioimmunotherapyinrectalcancerbytriggeringendoplasmicreticulumstressandcgasstingactivation AT lijinluan methylglyoxalfromgutmicrobesboostsradiosensitivityandradioimmunotherapyinrectalcancerbytriggeringendoplasmicreticulumstressandcgasstingactivation AT zhangda methylglyoxalfromgutmicrobesboostsradiosensitivityandradioimmunotherapyinrectalcancerbytriggeringendoplasmicreticulumstressandcgasstingactivation AT wujunxin methylglyoxalfromgutmicrobesboostsradiosensitivityandradioimmunotherapyinrectalcancerbytriggeringendoplasmicreticulumstressandcgasstingactivation |