Mitch Leslie in Science:
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.
…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.