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- MED12 loss activates endogenous retroelements to sensitise immunotherapy in pancreatic cancer
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Pancreas
Original research
MED12 loss activates endogenous retroelements to sensitise immunotherapy in pancreatic cancer
- Yingying Tang1,
- Shijie Tang2,
- Wenjuan Yang1,
- Zhengyan Zhang1,
- Teng Wang2,
- Yuyun Wu2,
- Junyi Xu1,
- Christian Pilarsky3,
- Massimiliano Mazzone4,5,
- Lei-Wei Wang6,
- http://orcid.org/0000-0002-5937-634XYongwei Sun7,
- Ruijun Tian8,
- Yujie Tang9,
- Yu Wang6,
- http://orcid.org/0000-0003-2346-2884Chaochen Wang2,10,11,
- http://orcid.org/0000-0002-6497-1792Jing Xue1
- 1State Key Laboratory of Systems Medicine for Cancer, Stem Cell Research Center, Ren Ji Hospital, Shanghai Cancer Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- 2Centre of Biomedical Systems and Informatics, ZJU-UoE Institute, Zhejiang University School of Medicine, International Campus, Zhejiang University, Haining, Zhejiang, China
- 3Department of Surgery, Universitätsklinikum Erlangen, Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), Erlangen, Germany
- 4Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology, VIB, Leuven, Belgium, Leuven, Belgium
- 5Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology, Department of Oncology, Leuven, Belgium
- 6Department of Oncology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- 7Department of Biliary and Pancreatic Surgery, Shanghai Jiao Tong University School of Medicine Affiliated Renji Hospital, Shanghai, China
- 8Shenzhen Key Laboratory of Functional Proteomics, Guangming Advanced Research Institute, Southern University of Science and Technology, Shenzhen, China
- 9Key Laboratory of Cell Differentiation and Apoptosis of National Ministry of Education, Shanghai Key Laboratory of Reproductive Medicine, Department of Histoembryology, Genetics and Developmental Biology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- 10Department of Breast Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, Hangzhou, China
- 11Biomedical and Health Translational Research Centre, Zhejiang University, Zhejiang, China
- Correspondence to Jing Xue, State Key Laboratory of Systems Medicine for Cancer, Stem Cell Research Center, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; xuejing0904{at}126.com; Dr Chaochen Wang; chaochenwang{at}intl.zju.edu.cn; Dr Yu Wang; wangyu4tc{at}163.com; Dr Yujie Tang; yujietang{at}shsmu.edu.cn
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.
- cancer immunobiology
- cellular immunity
- pancreatic cancer
Data availability statement
Data are available on reasonable request. All genomic sequencing data involved in this study have been deposited in the Gene Expression Omnibus database with the accession code GSE242098.
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- cancer immunobiology
- cellular immunity
- pancreatic cancer
Data availability statement
Data are available on reasonable request. All genomic sequencing data involved in this study have been deposited in the Gene Expression Omnibus database with the accession code GSE242098.
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Footnotes
YT, ST and WY contributed equally.
Contributors YYT and JX designed the experiments and interpreted the data; YYT and WJY performed most of the experiments; SJT, TW and YYW performed the bioinformatics analysis under the guidance of CCW; YW performed the retrospective study; ZYZ, and JYX, assisted in some experiments; YJT, YWS, LWW, RJT, MM and CP provided the key materials and assisted in some discussions; YYT and JX wrote the manuscript; JX and CCW provided overall guidance. Jing Xue acted as guarantor.
Funding This work was supported by the National Natural Science Foundation of China (no. 81970553, no. 81770628, no. 82022049, JXue), Shanghai Municipal Education Commission-Gaofeng Clinical Medicine Grant Support (no. 20161312, JXue), the Innovative Research Team of High-Level Local Universities in Shanghai, 111 project (no. B21024, JXue).
Competing interests None declared.
Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.
Provenance and peer review Not commissioned; externally peer reviewed.
Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.
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