• Gut Microbiome Determines Efficacy of Cancer Immunotherapy

Gut Microbiome Determines Efficacy of Cancer Immunotherapy

Specific groups of intestinal microbes can boost the anti-tumor effects of cancer immunotherapies in mice, researchers show.

Cancer immunotherapies that block immune inhibitory pathways have been tested in patients with several tumor types, but responses have varied.

A study published in Science, while not the first to link gut microbes with the efficacy of cancer therapy, associates the composition of the intestinal microbiome with the anti-tumor immunotherapy response and provides evidence for the effects of specific bacterial species.

Marie Vetizou et al studied the efficacy of the immunotherapy agent ipilimumab against established sarcomas in mice. Ipilimumab is a monoclonal antibody against CTLA4a negative regulator of T-cell activation. The antibody often produces immune-related adverse events at sites exposed to commensal microorganisms—mostly in the intestine. Many patients treated with ipilimumab develop antibodies to components of the enteric flora.

Vetizou et al therefore investigated the effects of this drug on growth of tumors implanted in mice with variations in intestinal bacteria, wrote Science News. They found that ipilimumab slowed growth of established MCA205 sarcomas in specific pathogen-free (SPF) but not germ-free (GF) mice. Moreover, a combination of broad-spectrum antibiotics (ampicillin, colistin, and streptomycin), as well as imipenem alone, but not colistin, compromised the anti-tumor effects of ipilimumab.

In mice and patients, T-cell responses specific for Bacteroides thetaiotaomicron or Bacteroides fragilis were associated with the efficacy of ipilimumab.

The authors performed high-throughput pyrosequencing of 16S ribosomal RNA gene amplicons in feces, and found that a single injection of ipilimumab significantly affected the microbiome at the genus level, inducing a rapid under-representation of Bacteroidales and Burkholderiales with a relative increase of Clostridiales.

The researchers then took fecal samples from 25 individuals with metastatic melanoma and categorized them based on the presence of Bacteroidales. The authors transplanted these fecal samples into GF mice, and 2 weeks later, gave them ipilimumab. Tumors growing in mice that had been transplanted with feces from patients with a higher percentage of B fragilis responded better to the drug than their counterparts.

“What was quite exciting for us is that using microbes may be a way to improve the efficacy of immunotherapies without increasing their toxic side effects,” study co- author Mathias Chamaillard (Center of Infection and Immunity, University of Lille, France) told The Scientist.

The discovery “opens up novel ways to potentially augment therapy,” Cynthia Sears (Johns Hopkins School of Medicine) told Science News. For example, it might be possible to increase a patient’s anti-tumor response with probiotics.

Further studies are needed to determine how the microbes boost the immune response—gut bacteria are involved in immune system development, but researchers aren’t sure how they modify its function in mature animals.

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