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Gut microbiota-derived hexa-acylated lipopolysaccharides enhance cancer immunotherapy responses

ABSTRACT: The gut microbiome modulates immunotherapy treatment responses, and this may explain why immune checkpoint inhibitors (ICI), such as anti-PD-1, are only effective in some patients. Previous studies correlated lipopolysaccharide (LPS)-producing gut microbes with poorer prognosis; however, LPS from diverse bacterial species can range from immunostimulatory to inhibitory. By functionally analyzing fecal metagenomes from 112 melanoma patients, we found that a subset of LPS-producing bacteria encoding immunostimulatory hexa-acylated LPS was enriched in microbiomes of clinical responders. In an implanted tumor mouse model of anti-PD-1 treatment, microbiota-derived hexa-acylated LPS was required for effective anti-tumor immune responses, and LPS-binding antibiotics and a small molecule TLR4 antagonist abolished anti-PD-1 efficacy. Conversely, oral administration of hexa-acylated LPS to mice significantly augmented anti-PD-1-mediated anti-tumor immunity. Penta-acylated LPS did not improve anti-PD-1 efficacy in vivo and inhibited hexa-acylated LPS-induced immune activation in vitro. Microbiome hexa-acylated LPS therefore represents an accessible predictor and potential enhancer of immunotherapy responses.

INSTRUMENT(S): 6546 Q-TOF LC/MS (Agilent Instrument model)

ORGANISM(S): Klebsiella Pneumoniae (ncbitaxon:573) Escherichia Coli (ncbitaxon:562)

SUBMITTER: Virginia A. Pedicord

PROVIDER: MSV000096803 | MassIVE | Wed Jan 08 06:52:00 GMT 2025

REPOSITORIES: MassIVE

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