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High-dose Vitamin C inhibits PD-L1 expression by activating AMPK in colorectal cancer
Jia Huang1, Su Min1, Ruiyang Hong1
1Department of Anesthesiology, Technology Innovation Research Center, the First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China.
Abstract:
Vitamin C (VitC) has elicited considerable interest regarding its potential role in cancer therapy; however, its effects on tumor immunity remain unclear. In colorectal cancer (CRC), although anti-PD-1/PD-L1 therapies demonstrate promise, their efficacy is still constrained. Our prior research demonstrated that VitC can inhibit tumor growth by suppressing the Warburg effect. This study aims to explore the effects of high-dose VitC on PD-L1 expression in CRC, focusing on its underlying mechanisms and potential for enhancing immunotherapy. We found that VitC inhibits aerobic glycolysis in HCT116 cells while also downregulating PD-L1 expression. Further investigations indicated that this process is mediated by VitC's activation of AMPK, which downregulates HK2 and NF-κB, ultimately resulting in reduced PD-L1 expression and increased T cell infiltration. Notably, we observed that VitC and the PD-L1 monoclonal antibody atezolizumab exhibit comparable tumor-inhibiting abilities, and their combined use further enhances this efficacy. In conclusion, our results demonstrate that high-dose VitC activates AMPK, downregulates PD-L1 expression, mitigates immune evasion, and suppresses tumor growth. This provides a promising strategy for optimizing immunotherapy in CRC.
Insights
High-dose Vitamin C (VitC) suppresses colorectal cancer growth by inhibiting the Warburg effect and downregulating PD-L1 expression. This enhances anti-tumor immunity and shows promise for improving cancer immunotherapy.
Area of Science:
- Oncology
- Immunology
- Biochemistry
Background:
- Colorectal cancer (CRC) immunotherapy, particularly anti-PD-1/PD-L1, shows promise but has limitations.
- Vitamin C (VitC) may play a role in cancer therapy, but its impact on tumor immunity is not fully understood.
- Previous research indicated VitC inhibits tumor growth by suppressing the Warburg effect.
Purpose of the Study:
- To investigate the effects of high-dose Vitamin C on PD-L1 expression in colorectal cancer.
- To elucidate the underlying mechanisms by which VitC influences PD-L1 expression and tumor immunity.
- To evaluate the potential of VitC in enhancing immunotherapy efficacy for CRC.
Main Methods:
- Assessed the impact of VitC on aerobic glycolysis and PD-L1 expression in HCT116 colorectal cancer cells.
- Investigated the role of AMPK activation in mediating VitC's effects on PD-L1.
- Examined the influence of VitC on HK2 and NF-κB signaling pathways.
- Compared the efficacy of VitC and atezolizumab (anti-PD-L1) alone and in combination.
Main Results:
- Vitamin C inhibited aerobic glycolysis and downregulated PD-L1 expression in HCT116 cells.
- VitC activated AMPK, leading to reduced HK2 and NF-κB expression, which in turn decreased PD-L1 levels.
- Downregulation of PD-L1 by VitC resulted in increased T cell infiltration.
- VitC and atezolizumab demonstrated comparable tumor-inhibiting effects, with combination therapy showing enhanced efficacy.
Conclusions:
- High-dose Vitamin C activates AMPK, downregulating PD-L1 expression and mitigating immune evasion in colorectal cancer.
- VitC demonstrates potential as an adjuvant therapy to enhance the efficacy of PD-L1 targeted immunotherapy in CRC.
- This study provides a promising strategy for optimizing immunotherapy outcomes in colorectal cancer patients.
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