Checkpoint inhibitors, which aim to unleash the power of the immune system on tumors, are some of the most impressive new cancer treatments. But most patients who receive them don’t benefit. Two new studies of mice suggest a surprising reason why—these people may not have the right mixture of bacteria in their guts. Both studies demonstrate that the composition of the gut microbiome—the swarms of microorganisms naturally dwelling in the intestines—determines how effective these cancer immunotherapies are.
The studies are the first to link our intestinal denizens to the potency of checkpoint inhibitors, drugs that thwart one of cancer’s survival tricks. To curb attacks on our own tissues, immune cells carry receptors that dial down their activity. But tumor cells can also stimulate these receptors, preventing the immune system from attacking them. Checkpoint inhibitors like ipilimumab—which has been on the market since 2011—nivolumab, and pembrolizumab stop tumor cells from stimulating the receptors.
The new work could change how doctors use the drugs. “Both of the papers show convincingly that microbes can affect the treatments,” says immunologist Yasmine Belkaid of the National Institute of Allergy and Infectious Disease in Bethesda, Maryland, who wasn’t connected to the new studies. In the past, researchers have typically looked for mutations in patients’ genomes that might explain why a particular checkpoint inhibitor isn’t working, says 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 can shrink tumors and extend patients’ lives, sometimes by years. Yet only a fraction of recipients improve. About 20% of melanoma patients treated with ipilimumab live longer, for example. Researchers don’t know what distinguishes them from the other 80%.
A side effect of the drug steered oncoimmunologist Laurence Zitvogel of the Gustave Roussy Cancer Campus in Villejuif, France, and colleagues toward the microbiome. Ipilimumab often triggers colitis, an inflammation of the large intestine, where part of our microbiome lives. That side effect suggests checkpoint inhibitors and the microbiome interact. Following up on that possibility, the researchers tracked the growth of tumors implanted in mice lacking intestinal bacteria. The checkpoint inhibitor they tested was less powerful in the animals.
Further analysis by Zitvogel and colleagues suggested that certain bacteria in the Bacteroides and Burkholderia genera were responsible for the antitumor effect of the microbiome. To confirm that possibility, the researchers transferred the microbes into mice that had no intestinal bacteria, either by feeding the microorganisms to the animals or giving them the Bacteroides-rich feces of some ipilimumab-treated patients. In both cases, an influx of microbes strengthened the animals’ response to one checkpoint inhibitor. “Our immune system can be mobilized by the trillions of bacteria we have in our gut,” Zitvogel says.
Immunologist Thomas Gajewski of the University of Chicago (UC) in Illinois and colleagues came to a similar conclusion after noticing a disparity between mice they had obtained from two suppliers. Melanoma tumors grew slower in mice from Jackson Laboratory than in mice from Taconic Farms. The microbiomes of rodent cagemates tend to homogenize—the animals eat each other’s feces—so the researchers housed mice from both suppliers together. Cohabitation erased the difference in tumor growth, indicating it depends on the types of microbes in the rodents’ guts.
When they analyzed the microbiomes of the mice, the researchers pinpointed a bacterial genus known as the Bifidobacterium. The team found that feeding mice from Taconic Farms a probiotic that contains several Bifidobacterium species increased the efficiency of a checkpoint inhibitor against tumors. “The endogenous antitumor response is significantly influenced by your commensal bacteria,” says co-author Ayelet Sivan, who was a Ph.D. student at UC when the research was conducted. Both groups reported their results online today in Science.
The two teams implicated different bacterial groups, but that 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. He adds that the new work complements a pair of 2013 studies that demonstrated that the microbiome affects how well chemotherapy works.
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. For example, it might be possible to beef up a patient’s antitumor response with probiotics. But researchers also see some potential roadblocks. As Zitvogel notes, regulatory agencies in the United States and Europe haven’t approved the use of probiotics for cancer patients. Also unclear is how the microbes boost the immune response—gut bacteria are key to the immune system’s development, but researchers aren’t sure how they tweak its function in mature animals. And scientists are just learning how to tinker with the microbiome. “It is not clear that we can meaningfully manipulate the microbiota and create positive health effects,” Sears says. Nonetheless, researchers say, the studies suggest that we may have some powerful new allies in the fight against cancer.