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TRABID inhibition activates cGAS/STING-mediated anti-tumor immunity through mitosis and autophagy dysregulation
Activation of tumor-intrinsic innate immunity has been a major strategy for improving immunotherapy. Previously, we reported an autophagy-promoting function of the deubiquitinating enzyme TRABID. Here, we identify a critical role of TRABID in suppressing anti-tumor immunity. Mechanistically, TRABID...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10220035/ https://www.ncbi.nlm.nih.gov/pubmed/37237031 http://dx.doi.org/10.1038/s41467-023-38784-z |
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author | Chen, Yu-Hsuan Chen, Han-Hsiun Wang, Won-Jing Chen, Hsin-Yi Huang, Wei-Syun Kao, Chien-Han Lee, Sin-Rong Yeat, Nai Yang Yan, Ruei-Liang Chan, Shu-Jou Wu, Kuen-Phon Chen, Ruey-Hwa |
author_facet | Chen, Yu-Hsuan Chen, Han-Hsiun Wang, Won-Jing Chen, Hsin-Yi Huang, Wei-Syun Kao, Chien-Han Lee, Sin-Rong Yeat, Nai Yang Yan, Ruei-Liang Chan, Shu-Jou Wu, Kuen-Phon Chen, Ruey-Hwa |
author_sort | Chen, Yu-Hsuan |
collection | PubMed |
description | Activation of tumor-intrinsic innate immunity has been a major strategy for improving immunotherapy. Previously, we reported an autophagy-promoting function of the deubiquitinating enzyme TRABID. Here, we identify a critical role of TRABID in suppressing anti-tumor immunity. Mechanistically, TRABID is upregulated in mitosis and governs mitotic cell division by removing K29-linked polyubiquitin chain from Aurora B and Survivin, thereby stabilizing the entire chromosomal passenger complex. TRABID inhibition causes micronuclei through a combinatory defect in mitosis and autophagy and protects cGAS from autophagic degradation, thereby activating the cGAS/STING innate immunity pathway. Genetic or pharmacological inhibition of TRABID promotes anti-tumor immune surveillance and sensitizes tumors to anti-PD-1 therapy in preclinical cancer models in male mice. Clinically, TRABID expression in most solid cancer types correlates inversely with an interferon signature and infiltration of anti-tumor immune cells. Our study identifies a suppressive role of tumor-intrinsic TRABID in anti-tumor immunity and highlights TRABID as a promising target for sensitizing solid tumors to immunotherapy. |
format | Online Article Text |
id | pubmed-10220035 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-102200352023-05-28 TRABID inhibition activates cGAS/STING-mediated anti-tumor immunity through mitosis and autophagy dysregulation Chen, Yu-Hsuan Chen, Han-Hsiun Wang, Won-Jing Chen, Hsin-Yi Huang, Wei-Syun Kao, Chien-Han Lee, Sin-Rong Yeat, Nai Yang Yan, Ruei-Liang Chan, Shu-Jou Wu, Kuen-Phon Chen, Ruey-Hwa Nat Commun Article Activation of tumor-intrinsic innate immunity has been a major strategy for improving immunotherapy. Previously, we reported an autophagy-promoting function of the deubiquitinating enzyme TRABID. Here, we identify a critical role of TRABID in suppressing anti-tumor immunity. Mechanistically, TRABID is upregulated in mitosis and governs mitotic cell division by removing K29-linked polyubiquitin chain from Aurora B and Survivin, thereby stabilizing the entire chromosomal passenger complex. TRABID inhibition causes micronuclei through a combinatory defect in mitosis and autophagy and protects cGAS from autophagic degradation, thereby activating the cGAS/STING innate immunity pathway. Genetic or pharmacological inhibition of TRABID promotes anti-tumor immune surveillance and sensitizes tumors to anti-PD-1 therapy in preclinical cancer models in male mice. Clinically, TRABID expression in most solid cancer types correlates inversely with an interferon signature and infiltration of anti-tumor immune cells. Our study identifies a suppressive role of tumor-intrinsic TRABID in anti-tumor immunity and highlights TRABID as a promising target for sensitizing solid tumors to immunotherapy. Nature Publishing Group UK 2023-05-26 /pmc/articles/PMC10220035/ /pubmed/37237031 http://dx.doi.org/10.1038/s41467-023-38784-z Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Chen, Yu-Hsuan Chen, Han-Hsiun Wang, Won-Jing Chen, Hsin-Yi Huang, Wei-Syun Kao, Chien-Han Lee, Sin-Rong Yeat, Nai Yang Yan, Ruei-Liang Chan, Shu-Jou Wu, Kuen-Phon Chen, Ruey-Hwa TRABID inhibition activates cGAS/STING-mediated anti-tumor immunity through mitosis and autophagy dysregulation |
title | TRABID inhibition activates cGAS/STING-mediated anti-tumor immunity through mitosis and autophagy dysregulation |
title_full | TRABID inhibition activates cGAS/STING-mediated anti-tumor immunity through mitosis and autophagy dysregulation |
title_fullStr | TRABID inhibition activates cGAS/STING-mediated anti-tumor immunity through mitosis and autophagy dysregulation |
title_full_unstemmed | TRABID inhibition activates cGAS/STING-mediated anti-tumor immunity through mitosis and autophagy dysregulation |
title_short | TRABID inhibition activates cGAS/STING-mediated anti-tumor immunity through mitosis and autophagy dysregulation |
title_sort | trabid inhibition activates cgas/sting-mediated anti-tumor immunity through mitosis and autophagy dysregulation |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10220035/ https://www.ncbi.nlm.nih.gov/pubmed/37237031 http://dx.doi.org/10.1038/s41467-023-38784-z |
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