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Low-protein diet enhances antitumor immunity in pancreatic cancer through microbiota-derived UDP-galactose
Yueying Chen1,2,3, Fulin Nian1,2, Shengdi Wu1,2
1Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai, China.
Abstract:
Dietary interventions can influence cancer progression, yet the role of low-protein diets (LPDs) in pancreatic ductal adenocarcinoma (PDAC) immunotherapy is unclear. Here we show that an LPD suppresses PDAC progression in male mice by remodeling the gut microbiota and activating antitumor immunity. LPD promoted immune activation and drove an immunostimulatory tumor-associated macrophage phenotype. Microbiota depletion abolished these effects and fecal microbiota transplantation from LPD-fed donors transferred the protective phenotype to recipients. Mechanistically, LPD enriched Blautia coccoides, which produced uridine diphosphate (UDP)-galactose to activate the macrophage P2Y14R-STAT1 axis, inducing an immunostimulatory phenotype. Combining LPD, B. coccoides or UDP-galactose with anti-PD1 improved survival over anti-PD1 alone. In persons with advanced PDAC, reduced fecal B. coccoides and serum UDP-galactose correlated with poor outcomes. These findings establish that LPD reshapes the gut microbiota and metabolites to enhance antitumor immunity through the UDP-galactose-P2Y14R-STAT1 axis, offering a dietary strategy to improve PDAC immunotherapy.
Insights
A low-protein diet (LPD) suppresses pancreatic cancer in mice by altering gut bacteria and boosting immune response. This dietary strategy enhances immunotherapy effectiveness by targeting the gut microbiota and its metabolites.
Area of Science:
- Immunology
- Microbiology
- Oncology
Background:
- Dietary interventions impact cancer progression.
- The role of low-protein diets (LPDs) in pancreatic ductal adenocarcinoma (PDAC) immunotherapy remains unclear.
Purpose of the Study:
- To investigate the effects of LPD on PDAC progression and immunotherapy in a preclinical model.
- To elucidate the mechanisms by which LPD influences the gut microbiota and antitumor immunity.
Main Methods:
- Utilized a mouse model of PDAC, employing microbiota depletion and fecal microbiota transplantation.
- Analyzed changes in gut microbiota composition, macrophage phenotype, and immune activation.
- Investigated the role of specific bacterial metabolites, such as uridine diphosphate (UDP)-galactose, and their signaling pathways (P2Y14R-STAT1 axis).
Main Results:
- LPD suppressed PDAC progression in male mice by remodeling the gut microbiota and activating antitumor immunity.
- LPD induced an immunostimulatory tumor-associated macrophage phenotype, dependent on gut microbiota.
- Enrichment of Blautia coccoides in LPD-fed mice produced UDP-galactose, activating the P2Y14R-STAT1 axis in macrophages.
- Combination therapy of LPD, B. coccoides, or UDP-galactose with anti-PD1 improved survival compared to anti-PD1 alone.
- Reduced fecal B. coccoides and serum UDP-galactose correlated with poor outcomes in patients with advanced PDAC.
Conclusions:
- LPD reshapes the gut microbiota and metabolites to enhance antitumor immunity.
- The UDP-galactose-P2Y14R-STAT1 axis is a key mediator of LPD's immunomodulatory effects in PDAC.
- LPD represents a potential dietary strategy to improve the efficacy of PDAC immunotherapy.
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