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Updated: Jun 14, 2025
Flow Cytometry-Based Isolation and Therapeutic Evaluation of Tumor-Infiltrating Lymphocytes in a Mouse Model of Pancreatic Cancer
Published on: January 17, 2025
MED12 loss activates endogenous retroelements to sensitise immunotherapy in pancreatic cancer
Yingying Tang1, Shijie Tang2, Wenjuan Yang1
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.
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.
Insights
MED12 epigenetically silences retrotransposons, suppressing immune responses in pancreatic cancer. Its loss enhances anti-cancer immunity and immunotherapy effectiveness, offering a new therapeutic target for pancreatic ductal adenocarcinoma (PDAC).
Area of Science:
- Cancer Biology
- Immunology
- Epigenetics
Background:
- Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal cancer with limited treatment options, particularly regarding immune checkpoint blockade (ICB) immunotherapy.
- Epigenetic dysregulation is crucial in cancer development and immune surveillance, but its role in PDAC remains poorly understood.
- Understanding factors that modulate immune surveillance is critical for improving PDAC treatment strategies.
Purpose of the Study:
- To identify key epigenetic factors influencing immune surveillance in pancreatic ductal adenocarcinoma (PDAC).
- To investigate the role of MED12 in regulating the tumor microenvironment (TME) and immune cell infiltration in PDAC.
- To explore the therapeutic potential of targeting MED12 for enhancing immunotherapy efficacy in PDAC.
Main Methods:
- Utilized an in vivo epigenetic-focused CRISPR-Cas9 screen in mouse PDAC models.
- Engrafted tumors in both immunocompetent and immunodeficient mice to assess immune modulation.
- Investigated the molecular mechanisms by which MED12 regulates gene expression and immune responses.
Main Results:
- MED12 was identified as a significant negative modulator of the immune tumor microenvironment (TME) in PDAC.
- Loss of MED12 promoted infiltration and cytotoxicity of immune cells (CD8+ T cells, NK cells), enhancing ICB treatment sensitivity.
- MED12 stabilizes heterochromatin, repressing retrotransposons; MED12 loss derepresses retrotransposons, activating type I interferon pathways and creating an inflamed TME.
- A negative correlation was observed between MED12 expression and immune response pathways, retrotransposon levels, and patient prognosis in PDAC treated with ICB.
Conclusions:
- MED12 plays a critical role in shaping the immune TME by epigenetically silencing retrotransposons in PDAC.
- Targeting MED12 offers a potential strategy to enhance tumor immunogenicity and overcome resistance to immunotherapy in PDAC.
- These findings highlight MED12 as a promising therapeutic target for improving outcomes in pancreatic cancer patients.
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