Researchers around the world are studying new cancer immunotherapies and their relation to the microbiome, the collection of bacteria and other organisms that live inside of every human body. French and U.S. researchers say that good gut bacteria can help shrink tumors for cancer patients receiving an immunotherapy called PD-1.
According to an article in Science, checkpoint inhibitors have seen remarkable success in solid tumors, yet only 25% of patients respond to PD-1 blockers. In 2015, a French team of researchers, led by immunologist Laurence Zitvogel of the Gustave Roussy Cancer Campus in Villejuif, France, reported that changing the gut microbiome of a mouse could make its tumors respond better to a checkpoint blocker. A second group reported that different gut microbes explained why mice from two different suppliers responded differently to PD-1 blockers. According to the article:
In one of the new papers, Zitvogel’s group examined data for 249 lung, kidney, and bladder cancer patients, 69 of whom took antibiotics for routine reasons such as dental work or a urinary tract infection before or soon after starting a PD-1 drug. The results were striking: Patients on antibiotics, which disrupt the gut microbiome, relapsed sooner and didn’t live as long. Zitvogel’s team then looked for differences in the gut bacteria of patients who did or did not respond well. In the responders, they fingered Akkermansia muciniphila, a species associated with the gut’s mucus lining that may protect against obesity and diabetes. When germ-free mice with no gut bacteria received fecal transplants from responders, they did better on PD-1 blockers than did mice given nonresponder feces. And poorly responding mice could be turned into responders by feeding them A. muciniphila.
The gut microbiome also matters in melanoma patients receiving PD-1 blockers, a team led by Jennifer Wargo of MD Anderson Cancer Center in Houston, Texas, reports in the other paper: Responders had a more diverse microbiome and more of specific bacteria. Her group also found that giving mice fecal transplants from patients who did or did not respond to the drugs led to similar outcomes in the animals.
The beneficial bugs in Wargo’s study were different from those in France—mainly Faecalibacteriumand Clostridiales. One reason could be that our microbiomes vary depending on geography and diet, says molecular biologist Scott Bultman of the University of North Carolina in Chapel Hill. “There is a certain amount of overlap” between the species identified by the two teams, he adds.
Patients who responded in the above studies had a richer, more diverse microbiome than those who did not. Different levels of bacteria made a difference as well.
High levels of Faecalibacterium and Clostridiales appeared to be beneficial, while Bacteroidales species were bad news in the study.
The good bacteria may help prime the T cells to fight cancer cells. Zitovogel’s team found that a signaling cytokine called IL12 that is released in response to A. munciniphilia increased the recruitment of CCR9+CXCR3+CD4+ T lymphocytes into tumor beds. “They are educated by the good bugs that you have added,” says Wargo.
The French group estimates that avoiding antibiotics while taking PD-1 blockers could boost patient responses from 25-40%.
According to the University of Washington, we humans are mostly microbes, over 100 trillion of them. Microbes outnumber our human cells ten to one. The majority live in our gut, particularly in the large intestine The microbiome is the genetic material of all the microbes – bacteria, fungi, protozoa and viruses – that live on and inside the human body. The number of genes in all the microbes in one person’s microbiome is 200 times the number of genes in the human genome. The microbiome may weigh as much as five pounds. The bacteria in the microbiome help digest our food, regulate our immune system, protect against other bacteria that cause disease, and produce vitamins including B vitamins B12, thiamine and riboflavin, and Vitamin K, which is needed for blood coagulation. The microbiome was not generally recognized to exist until the late 1990s
Experts say that the discovery has great implications in cancer immunotherapy. Dr. Jennifer Wargo, from Texas said “The microbiome is game-changing, not just cancer but for overall health, it’s definitely going to be a major player.”
More research needs to be done to determine if treatment responses could improve in the presence of good gut bacteria for other immunotherapies like vaccines, CAR T cell treatments or monoclonal antibodies, but it presents a fascinating area of study for cancer researchers.