Sucralose Consumption Ablates Cancer Immunotherapy Response through Microbiome Disruption
Kristin M. Morder, Madison Nguyen, Drew N. Wilfahrt, Zakaria Larbi Dahmani, Ansen B.P. Burr, Bingxian Xie, Michael Morikone, Hector Nieves-Rosado, William G. Gunn, Drew E. Hurd, Hong Wang, Steven J. Mullett, Kaitlin Bossong, Stacy G. Wendell, Dhivyaa Rajasundaram, Larry Kane, Greg M. Delgoffe, Jishnu Das, Diwakar Davar, Abigail E. Overacre-Delgoffe
Abstract
Gut microbiota composition is directly associated with response to immunotherapies in cancer. The impact of diet on the gut microbiota and downstream immune responses to cancer remains unclear. In this study, we show that consumption of a common nonnutritive sweetener, sucralose, modifies microbiome composition, restricts T-cell metabolism and function, and limits immunotherapy response in preclinical models of cancer and patients with advanced cancer treated with anti-PD-1-based immune checkpoint inhibitors. Sucralose consumption is associated with a reduction in microbiota-accessible arginine, and amino acid supplementation or fecal microbiome transfer from anti-PD-1 responder mice completely restores T-cell function and immunotherapy response. Overall, sucralose consumption destabilizes the gut microbiota, resulting in compromised T-cell function and ablated immune checkpoint inhibitor response in cancer. SIGNIFICANCE: This study highlights an unappreciated role of sucralose in reducing immunotherapy efficacy in both mouse models and samples from patients with cancer through shifts in the microbiome and arginine degradation that lead to T-cell exhaustion. T-cell function and immunotherapy responses are restored through amino acid supplementation. See related commentary by Chandra et al., p. 2196.