Proteobacteria impair anti-tumor immunity in the omentum by consuming arginine

• Published in: Cell host & microbe Vol. 32; no. 7; pp. 1177 - 1191.e7
• Main Authors: Meza-Perez, Selene, Liu, Mingyong, Silva-Sanchez, Aaron, Morrow, Casey D., Eipers, Peter G., Lefkowitz, Elliot J., Ptacek, Travis, Scharer, Christopher D., Rosenberg, Alexander F., Hill, Dave D., Arend, Rebecca C., Gray, Michael J., Randall, Troy D.
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 10.07.2024
• Subjects: anti-tumor responses; arginine metabolism; gut Proteobacteria; mTOR pathway; omentum; Treg activation; Treg activation; mTOR pathway; gut Proteobacteria; arginine metabolism; omentum; anti-tumor responses
• ISSN: 1931-3128; 1934-6069; 1934-6069
• DOI: 10.1016/j.chom.2024.06.003

Gut microbiota influence anti-tumor immunity, often by producing immune-modulating metabolites. However, microbes consume a variety of metabolites that may also impact host immune responses. We show that tumors grow unchecked in the omenta of microbe-replete mice due to immunosuppressive Tregs. By contrast, omental tumors in germ-free, neomycin-treated mice or mice colonized with altered Schaedler’s flora (ASF) are spontaneously eliminated by CD8+ T cells. These mice lack Proteobacteria capable of arginine catabolism, causing increases in serum arginine that activate the mammalian target of the rapamycin (mTOR) pathway in Tregs to reduce their suppressive capacity. Transfer of the Proteobacteria, Escherichia coli (E. coli), but not a mutant unable to catabolize arginine, to ASF mice reduces arginine levels, restores Treg suppression, and prevents tumor clearance. Supplementary arginine similarly decreases Treg suppressive capacity, increases CD8+ T cell effectiveness, and reduces tumor burden. Thus, microbial consumption of arginine alters anti-tumor immunity, offering potential therapeutic strategies for tumors in visceral adipose tissue. [Display omitted] •A metabolic link between gut microbiota and anti-tumor immunity in adipose tissue•Amount of Proteobacteria in the gut controls host arginine levels in circulation•Arginine reduces adipose-associated Treg suppressive function via mTOR•Arginine supplementation restores anti-tumor immunity independent of the microbiota Meza-Perez et al. link gut microbial diversity and anti-tumor immunity in the omentum (a visceral adipose tissue). Reduced arginine-consuming Proteobacteria in the gut elevate arginine in circulation, which increases mTOR expression in Tregs, thereby impairing Treg suppressive function, improving anti-tumor CD8+ T cell responses, and leading to tumor elimination.