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Published on: January 6, 2014
mTOR Inhibitors Can Enhance the Anti-Tumor Effects of DNA Vaccines through Modulating Dendritic Cell Function in the
Yu-Li Chen1, Han-Wei Lin2, Nai-Yun Sun3
1Department of Obstetrics and Gynecology, College of Medicine, National Taiwan University, Taipei City 100, Taiwan. uly1007@yahoo.com.tw.
Abstract:
The life span of dendritic cells (DCs) can become short following induced activation, which is associated with metabolic transition due to the regulation of mechanistic target of rapamycin (mTOR). The purpose of this study was to investigate the potential of inhibiting mTOR to modulate DC functions for elevating the anti-tumor effects of DNA vaccines. Therefore, the influences of various inhibitors of mTOR (mTORi) on the expressions of DC maturation markers, the abilities of antigen presenting and processing of BMM-derived DCs and the tumor killing effects of E7-specific CD8+ T lymphocytes activated by BMM-derived DCs were in vitro examined. The anti-tumor effects of connective tissue growth factor (CTGF)/E7 DNA vaccine and/or mTORi were also in vivo analyzed. In our study, suppressive effects of mTORi on the DC maturation markers expressed on BMMCs could be reversed. The mTORi-treated mature BMM-derived DCs tended to be non-apoptotic. These mTORi-treated BMM-derived DCs could have better antigen presenting and processing abilities. The E7-specific cytotoxic CD8+ T lymphocytes could have more potent tumoricidal activity following activation of mTORi-treated BMM-derived DCs. For tumor-bearing mice, those treated with CTGF/E7 DNA vaccine and mTORi indeed can have higher percentages of mature DCs in the TME, better disease control and longer survivals. Consequently, application of mTORi can be a pharmacological approach for temporally increasing life span, antigen presenting and antigen processing of DCs to strengthen the therapeutic outcome of cancer immunotherapy.
Insights
Inhibiting mechanistic target of rapamycin (mTOR) can extend dendritic cell (DC) lifespan and enhance their function. This approach improves anti-tumor immunity when combined with DNA vaccines, leading to better disease control and survival in mice.
Area of Science:
- Immunology
- Cancer Biology
- Pharmacology
Background:
- Dendritic cells (DCs) are crucial for initiating immune responses but have a limited lifespan after activation, influenced by metabolic regulation via mechanistic target of rapamycin (mTOR).
- Shortened DC lifespan can impede their ability to effectively stimulate anti-tumor immunity, particularly in the context of cancer vaccines.
Purpose of the Study:
- To investigate the impact of inhibiting mTOR (mTORi) on DC function and its potential to enhance the anti-tumor efficacy of DNA vaccines.
- To evaluate whether mTOR inhibition can modulate DC maturation, antigen presentation, and antigen processing capabilities.
Main Methods:
- In vitro analysis of various mTOR inhibitors (mTORi) on bone marrow-derived DC (BMM-derived DC) maturation markers, antigen-presenting, and processing abilities.
- In vitro assessment of E7-specific CD8+ T lymphocyte anti-tumor activity following activation by mTORi-treated DCs.
- In vivo evaluation of the anti-tumor effects of a connective tissue growth factor (CTGF)/E7 DNA vaccine combined with mTORi in tumor-bearing mice.
Main Results:
- mTORi reversed suppressive effects on DC maturation markers and promoted non-apoptotic, mature DCs.
- mTORi-treated DCs exhibited enhanced antigen-presenting and processing capabilities.
- Activation of E7-specific CD8+ T lymphocytes by mTORi-treated DCs resulted in more potent tumoricidal activity.
- Combination therapy with CTGF/E7 DNA vaccine and mTORi led to increased mature DCs in the tumor microenvironment (TME), improved disease control, and prolonged survival in mice.
Conclusions:
- Pharmacological inhibition of mTOR can be a strategy to increase the lifespan and functional capacity of DCs.
- Modulating DC function via mTOR inhibition can significantly strengthen the therapeutic outcomes of cancer immunotherapy, particularly DNA vaccines.
- This approach holds promise for enhancing anti-tumor immune responses and improving patient survival in cancer treatment.
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