How researchers are probing germ-free mice to elucidate this connection
One of the bright lights of cancer treatment in recent years has been immunotherapy, specifically a class of drugs known as immune checkpoint inhibitors. These drugs are designed to temporarily release the breaks on proteins that sit on the surface of T cells, freeing these immune cells to hunt down and destroy tumors.
Immune checkpoint inhibitors have worked amazingly well in about 20% of patients with cancer—shrinking and in some cases eliminating their tumors for extended periods of time. But what about the other 80% who have been prescribed this type of immunotherapy. Why haven’t they responded as well?
One possible explanation could lie in our gut. Theories abound about the role that the gut microbiome—the sum total of genetic material in the microorganisms that live in and on us—might be a key determinant in how well patients respond to these drugs. “It appears that the gut flora that we all have, and evolved with, can set our immune systems up in certain pro- or anti-inflammatory conditions,” says Bob Mihalek, Associate Director of Pharmacology, Oncology at Charles River Laboratories. “Because of the massive diversity in human population in terms of diet, exercise, exposure to environmental toxins, certain people may be predisposed to immune checkpoint inhibitors and not respond. It really is somewhat of a black box as to what these conditions are that would create a responder vs. a non-responder.”
One way Mihalek’s group is testing this theory is in germ-free mice, which are mice that have no microorganisms living in or on them. One way to view the germ-free mouse, says Mihalek, is as a blank slate. “Our job is to add some color, he says. “If we add, say, these five bacteria or ten bacteria back to the mouse, could we restore certain physiological processes that may have been absent. One of those processes might be responding to a checkpoint inhibitor.”
This process of sequentially adding back in a few bacteria at a time is painstaking but essential. “We have anywhere between 400 and 1000 species of bacteria living in our gut at any given time. Many of them can’t be cultured outside the gut. With that complexity, we can’t just go in and determine which ones are important. We need to add them in one by one.”
Mihalek says it may be possible, one day, to use certain species of bacteria as biomarkers for immunotherapy responses. “Once we are able to identify good bacteria vs. bad bacteria, then we can ask the obvious question: What are these bacteria doing,” says McHale. “Are they secreting metabolites that inhibit or activate the immune system?”
For more information on this connection between the microbiome and immunotherapy responses—and how germ-free mice are helping researchers interrogate this question, watch our video by clicking on the link above.