Quercetin-derived microbial metabolite DOPAC potentiates CD8+ T cell anti-tumor immunity via NRF2-mediated mitophagy
Penghu Han1, Shuzheng Chu2, Jing Shen1
1Department of Gastroenterology, Qilu Hospital of Shandong University, Advanced Medical Research Institute, Shandong University, Jinan 250012, China.
Abstract:
Quercetin, a dietary flavonol, shows promise in cancer prevention, though its effects on the immune compartment within the tumor microenvironment are not fully understood. Here, we identify 3,4-dihydroxyphenylacetic acid (DOPAC), a microbial metabolite of quercetin, as a critical mediator of its anti-tumor effects in a CD8+ T cell-dependent manner. Mechanistically, DOPAC directly binds to Kelch-like epichlorohydrin-associated protein 1 (KEAP1), disrupting its interaction with nuclear factor erythroid 2-related factor 2 (NRF2) and preventing KEAP1-mediated degradation of NRF2 in CD8+ T cells. Elevated NRF2 transcriptionally enhances the expression of B cell lymphoma 2-interacting protein 3, promoting mitophagy and mitochondrial functionality, which improves CD8+ T cell fitness within the tumor microenvironment. Furthermore, DOPAC synergizes with immune checkpoint blockade to suppress tumor growth. Our findings underscore the role of microbial metabolites of dietary nutrients in modulating anti-tumor immune responses, positioning DOPAC as a promising candidate for cancer immunotherapy.
Insights
Quercetin metabolite DOPAC enhances anti-tumor immunity by boosting CD8+ T cell function. This microbial metabolite shows promise for cancer immunotherapy, particularly when combined with immune checkpoint blockade.
Area of Science:
- Immunology
- Oncology
- Microbiology
Background:
- Quercetin, a dietary flavonol, has potential in cancer prevention.
- The impact of quercetin on the tumor microenvironment's immune cells is not fully understood.
Purpose of the Study:
- To identify quercetin metabolites mediating anti-tumor effects.
- To elucidate the mechanism by which these metabolites affect CD8+ T cells.
- To explore the therapeutic potential of these metabolites in cancer immunotherapy.
Main Methods:
- Identification of quercetin microbial metabolites.
- In vitro assays to assess metabolite binding to KEAP1 and NRF2 interaction.
- Analysis of NRF2-mediated gene expression in CD8+ T cells.
- Assessment of CD8+ T cell function and mitochondrial health.
- In vivo tumor models evaluating DOPAC efficacy alone and with immune checkpoint blockade.
Main Results:
- 3,4-dihydroxyphenylacetic acid (DOPAC), a quercetin metabolite, mediates anti-tumor effects dependent on CD8+ T cells.
- DOPAC binds KEAP1, preventing NRF2 degradation in CD8+ T cells.
- Elevated NRF2 enhances BCL2-interacting protein 3, promoting mitophagy and improving CD8+ T cell fitness.
- DOPAC synergizes with immune checkpoint blockade to inhibit tumor growth.
Conclusions:
- Microbial metabolism of dietary nutrients plays a key role in anti-tumor immunity.
- DOPAC enhances CD8+ T cell function and anti-tumor responses.
- DOPAC is a promising candidate for cancer immunotherapy, especially in combination therapies.
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