There were signs of this already. In 2013, two groups of scientists showed that three cancer drugs can mobilize the immune system to kill tumors, but only in the presence of the right gut microbes. Laurence Zitvogel at the Gustave-Roussy Cancer Campus, who led one of the two teams, wanted to see if the same was true for a new wave of promising immunotherapy drugs called checkpoint inhibitors.
These drugs work by unshackling T-cells—a class of immune cells that seek and destroy potential threats, cancers included. T-cells are typically muzzled by “checkpoint proteins” on their surface. By inhibiting these checkpoints, drugs like ipilimumab can remove the muzzles, and unleash packs of slavering, destructive T-cells upon the tumors.
But not, it seems, without the right gut bacteria. When Marie Vetizou, a member of Zitvogel's team, treated mice with antibiotics, which raze the gut of its native microbes, ipilimumab lost its sting. It failed to mobilize the usual T-cell army, and failed to keep the rodents' tumors under control. Similarly, the wonder drug didn't work on germ-free rodents that had been raised in the absence of microbes. “It was black and white,” says Zitvogel, presenting her work at the NCRI Cancer Conference in Liverpool. “There’s no longer efficacy of ipilimumab in the absence of the gut microbiota.”
Some bacteria are more important than others. The team found that two species—Bacteroides thetaiotamicron (B-theta, one of the most thoroughly studied gut microbes) and Bacteroides fragilis (B-frag, a potent anti-inflammatory bug)—managed to re-sensitize the mice to ipilimumab. The bacteria weren't even necessary: The mice also started responding to the drug after receiving T-cells that specifically recognized B-frag.
Does any of this matter to actual cancer patients? To find out, the team studied 25 people with advanced melanoma, and showed that ipilimumab changes their microbiome. It shifts the microbes from one distinctive community to another, each dominated by different species of Bacteroides. When the team transplanted the “after” communities into germ-free mice, these rodents responded well to ipilimumab; the “before” communities had no such effect. And once again, B-frag was especially important: The greater its numbers, the smaller the tumors.
But why does ipilimumab stimulate the growth of microbes that, in turn, make it more effective—and how? “Many important questions remain before these findings can be translated to human trials, though,” says Sarkis Mazmanian from the California Institute of Technology, an immunologist who has studied B-frag in the context of autism. “But the link between this cancer immunotherapy and the microbiome is very exciting.”
Meanwhile, a second team led by Thomas Gajewski at the University of Chicago took a different approach and ended up pointing in the same general direction. They first noticed that two strains of lab mice reacted very differently to melanomas. Those purchased from Jackson Laboratory (JAX) developed less aggressive tumors than those from Taconic Biosciences (TAC), because they spontaneously mounted a more vigorous T-cell response.