Microbes aid cancer drugs

A new class of cancer treatments that unleash the power of the immune system on tumors may depend on some unlikely allies. Two studies of mice in this week's issue of Science demonstrate that the gut microbiome—the swarms of microorganisms dwelling in the intestines—determines how effective these cancer immunotherapies are.

Known as checkpoint inhibitors, the therapies foil one of cancer's devious survival tricks: its ability to turn off the immune response that might otherwise attack tumor cells. Yet despite their promise, the drugs so far only help a minority of people with cancer. Researchers have suspected that genetic differences between patients might explain the varying responses, notes molecular biologist Scott Bultman of the University of North Carolina School of Medicine in Chapel Hill. The new results are encouraging, he says, because “it's easier to change your gut microbiota than your genome.”

Checkpoint inhibitors target molecules that are key to cancer's immune-blocking effect. Some tumor cells stimulate CTLA4, a receptor on T cells that dials down their activity; others don a protein called PD-L1 that stifles potential T cell attackers. Ipilimumab, a monoclonal antibody that in 2011 became the first checkpoint inhibitor to receive Food and Drug Administration approval, blocks CTLA4, whereas other therapies, such as nivolumab and pembrolizumab, target PD-L1 or its receptor.

Ipilimumab often triggers colitis, an inflammation of the large intestine, where part of our microbiome lives. This side effect suggested that checkpoint inhibitors could interact with the microbiome. To figure out whether they do, oncoimmunologist Laurence Zitvogel of the Gustave Roussy Cancer Campus in Villejuif, France, and colleagues tracked the growth of tumors implanted into mice lacking intestinal bacteria. They found that an antibody that blocks CTLA4 was less powerful in the animals.

The key missing microbes appeared to be bacteria in the Bacteroides and Burkholderia genera. Feeding those organisms to the microbe-free mice, either in pure form or in Bacteroides-rich feces from certain ipilimumab-treated patients, strengthened the animals' response to a CTLA4-inhibiting antibody. “Our immune system can be mobilized by the trillions of bacteria we have in our gut,” Zitvogel says.

A second team led by immunologist Thomas Gajewski of the University of Chicago in Illinois came to a similar conclusion after noticing that melanoma tumors grew slower in mice from one supplier than in mice from another. Caging the mice together so that their microbiomes could homogenize erased the difference in tumor growth, indicating that the bacteria in one set of mice had been aiding their immune system. This team pinpointed members of the genus Bifidobacterium as an immune helper: Feeding mice a probiotic that contains several Bifidobacterium species increased the efficiency of a PD-L1–blocking antibody against tumors.

The fact that the two teams implicated different bacterial groups doesn't worry microimmunologist Christian Jobin of the University of Florida College of Medicine in Gainesville. “Different drugs, different bugs, but the same endpoint,” he says.

Exactly how the microbiome bolsters the drugs remains unclear. Still, the discovery “opens up novel ways to potentially augment therapy,” says Cynthia Sears, an infectious disease specialist at Johns Hopkins School of Medicine in Baltimore, Maryland. Doctors could, for example, try to beef up antitumor responses with probiotics, although Zitvogel notes that regulatory agencies haven't approved their use for cancer patients.