MED12 loss activates endogenous retroelements to sensitise immunotherapy in pancreatic cancer
Tang Y, Tang S, Yang W, Zhang Z, Wang T, Wu Y, Xu J, Pilarsky C, Mazzone M, Wang LW, Sun Y, Tian R, Tang Y, Wang Y, Wang C, Xue J (2024)
Publication Type: Journal article
Publication year: 2024
Journal
Article Number: gutjnl-2024-332350
DOI: 10.1136/gutjnl-2024-332350
Abstract
Objective Pancreatic ductal adenocarcinoma (PDAC) stands as one of the most lethal cancers, marked by its lethality and limited treatment options, including the utilisation of checkpoint blockade (ICB) immunotherapy. Epigenetic dysregulation is a defining feature of tumourigenesis that is implicated in immune surveillance, but remains elusive in PDAC. Design To identify the factors that modulate immune surveillance, we employed in vivo epigenetic-focused CRISPR-Cas9 screen in mouse PDAC tumour models engrafted in either immunocompetent or immunodeficient mice. Results Here, we identified MED12 as a top hit, emerging as a potent negative modulator of immune tumour microenviroment (TME) in PDAC. Loss of Med12 significantly promoted infiltration and cytotoxicity of immune cells including CD8+ T cells, natural killer (NK) and NK1.1+ T cells in tumours, thereby heightening the sensitivity of ICB treatment in a mouse model of PDAC. Mechanistically, MED12 stabilised heterochromatin protein HP1A to repress H3K9me3-marked endogenous retroelements. The derepression of retrotransposons induced by MED12 loss triggered cytosolic nucleic acid sensing and subsequent activation of type I interferon pathways, ultimately leading to robust inflamed TME . Moreover, we uncovered a negative correlation between MED12 expression and immune resposne pathways, retrotransposon levels as well as the prognosis of patients with PDAC undergoing ICB therapy. Conclusion In summary, our findings underscore the pivotal role of MED12 in remodelling immnue TME through the epigenetic silencing of retrotransposons, offering a potential therapeutic target for enhancing tumour immunogenicity and overcoming immunotherapy resistance in PDAC.
Authors with CRIS profile
Involved external institutions
Renji Hospital / 仁济医院 / Rénjì Yīyuàn
China (CN)
Zhejiang University / Chekiang University / 浙江大学
China (CN)
Flanders Institute for Biotechnology / Vlaams Instituut voor Biotechnologie (VIB)
Belgium (BE)
Southern University of Science and Technology
China (CN)
Shanghai Jiao Tong University / 上海交通大学
China (CN)
China (CN)
Zhejiang University / Chekiang University / 浙江大学
China (CN)
Flanders Institute for Biotechnology / Vlaams Instituut voor Biotechnologie (VIB)
Belgium (BE)
Southern University of Science and Technology
China (CN)
Shanghai Jiao Tong University / 上海交通大学
China (CN)
How to cite
APA:
Tang, Y., Tang, S., Yang, W., Zhang, Z., Wang, T., Wu, Y.,... Xue, J. (2024). MED12 loss activates endogenous retroelements to sensitise immunotherapy in pancreatic cancer. Gut. https://doi.org/10.1136/gutjnl-2024-332350
MLA:
Tang, Yingying, et al. "MED12 loss activates endogenous retroelements to sensitise immunotherapy in pancreatic cancer." Gut (2024).
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