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Updated: Sep 15, 2025
A Genetically Engineered Mouse Model of Sporadic Colorectal Cancer
Published on: July 6, 2017
Ablating UNG activity in a mouse model inhibits colorectal cancer growth by increasing tumor immunogenicity
Eric S Christenson1,2, Brandon E Smith3, Thanh J Nguyen1,2
1Department of Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins.
Abstract:
Uracil DNA glycosylase (UNG) excises uracil and 5-fluorouracil bases from DNA and is implicated in fluorodeoxyuridine (FdU) resistance. Here we explore the effects of inhibiting UNG activity, or depleting the UNG protein, in 2 mouse syngeneic models for colorectal cancer. Overexpressing the small UNG inhibitor protein (UGI) in mismatch repair-deficient (MMR-deficient) MC38 cells injected into C57BL/6J mice delayed tumor growth and prolonged survival when combined with FdU. Combining UNG inhibition with FdU numerically increased CD4+ T lymphocytes and B cells compared with FdU or UNG inhibition alone, suggesting an immune component to the effects. In contrast, shRNA depletion of UNG in the absence of FdU treatment resulted in 70% of mice clearing their tumors, and a 3-fold increase in overall survival compared with FdU. Analysis of MC38 tumor-infiltrating immune cells showed UNG depletion increased monocyte and dendritic cell populations, with CD8+ T cells also numerically increased. shRNA depletion of UNG in MMR-proficient CT-26 cells injected into BALB/c mice produced minimal benefit; the addition of anti-PD-1 antibody synergized with UNG depletion to increase survival. Cytotoxic T cell depletion abolished the benefits of UNG depletion in both models. These findings suggest UNG inhibition and/or depletion could enhance antitumor immune responses in humans.
Insights
Inhibiting uracil DNA glycosylase (UNG) can enhance anti-tumor immunity. Depleting UNG in colorectal cancer models boosted immune cell activity and improved survival, suggesting potential for new cancer therapies.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Uracil DNA glycosylase (UNG) removes uracil from DNA and is linked to fluorodeoxyuridine (FdU) resistance in cancer.
- Targeting UNG may overcome FdU resistance and modulate anti-tumor immune responses.
Purpose of the Study:
- To investigate the impact of inhibiting or depleting UNG on colorectal cancer growth and immune responses in preclinical models.
- To assess the potential of UNG targeting as an immunotherapy strategy.
Main Methods:
- Utilized two mouse syngeneic models for colorectal cancer (MC38 and CT-26).
- Employed methods including overexpression of UNG inhibitor protein (UGI), shRNA-mediated UNG depletion, and combination therapies with FdU and anti-PD-1 antibodies.
- Analyzed tumor growth, survival rates, and tumor-infiltrating immune cell populations (e.g., T cells, B cells, monocytes, dendritic cells).
Main Results:
- UNG inhibition combined with FdU in MMR-deficient MC38 tumors delayed growth and increased survival, with enhanced CD4+ T cell and B cell infiltration.
- UNG depletion alone in MC38 tumors led to significant tumor clearance (70% of mice) and a 3-fold increase in survival, associated with increased monocytes, dendritic cells, and CD8+ T cells.
- In MMR-proficient CT-26 tumors, UNG depletion showed minimal benefit alone but synergized with anti-PD-1 therapy to improve survival; cytotoxic T cell depletion abrogated these benefits.
Conclusions:
- UNG inhibition or depletion can potentiate anti-tumor immune responses in colorectal cancer models.
- Targeting UNG may represent a viable strategy to enhance cancer immunotherapy, particularly in combination with existing treatments.
- The efficacy of UNG targeting is dependent on the tumor's mismatch repair status and can be modulated by immune checkpoint inhibitors.
