The Toll-like receptor 4 pathway modulates response to anti-PD-1 therapy

Abstract Immune checkpoint inhibitors (ICI), such as anti-PD-1, have revolutionized cancer treatment. The use of antibiotics can lead to abnormal gut microbiome composition resulting in primary resistance to ICI. However, the mechanism by which this occurs is poorly understood. Metagenomic analyses of melanoma patient stool samples prior to therapy revealed an association between clinical responses to anti-PD-1 and functional differences in gut bacteria, including Gram-negative bacteria capable of lipopolysaccharide biosynthesis. By modeling anti-PD-1 therapy in mice, we found an antibiotic that binds lipopolysaccharide inhibited therapeutic efficacy. Subsequently, the inhibition of TLR4 signaling resulted in a loss of anti-PD-1 efficacy. Oral supplementation with lipopolysaccharide augmented anti-PD-1 immunology responses. These results reveal a TLR4-dependent role for gut-derived lipopolysaccharide in modulating anti-PD-1 responses.