Gut Bacteria Can Dramatically Amplify Cancer Immunotherapy

The combination of oral doses of the bacteria and injections with anti-PD-L1 antibody nearly abolished tumor outgrowth, the researchers reported in Science (doi:10.1126/science.aac4255).

“Our results clearly demonstrate a significant, although unexpected, role for specific gut bacteria in enhancing the immune system’s response to melanoma and possibly many other tumor types,” said study director Thomas Gajewski, MD, PhD, professor of medicine and pathology at the University of Chicago in Illinois.

“The field has recently recognized close connections between the gut microbiome and the immune system,” he said. “This finding provides a novel way to exploit that connection, to improve immunotherapy by selectively modulating intestinal bacteria.”

Checkpoint inhibitors such as ipilimumab, nivolumab, and pembrolizumab have had a dramatic impact on treatment of several tumor types, including melanoma, lung cancer, head and neck cancers and others. But only one-third or fewer patients have a vigorous response. Cancer researchers have wondered why so few benefit.

Gajewski and colleagues found a similar pattern in the mice they use for cancer research. They noticed that mice purchased from Jackson Laboratory (JAX) tended to have a robust spontaneous immune response to small melanoma tumors implanted under their skin. Mice from Taconic Biosciences (TAC) showed only a weak immune response.

But when the researchers put the mice from both sources in cages together for 3 weeks, they found that co-housing “completely abolished the differences in tumor growth,” Gajewski said. This made them suspect that sharing exposure to various types of bacteria allowed the TAC mice to acquire microbes from JAX mice that somehow enhanced their immunity to tumors.

They confirmed their suspicion by collecting fecal matter from JAX mice and transferring it into the stomachs of TAC mice. It worked. Treated TAC mice were then able to mount a strong immune response and delay tumor growth. The reverse process, transferring fecal bacteria from TAC to JAX mice had no effect.

Next, they compared the effects of bacterial transfer against a checkpoint inhibitor, anti-PD-L1 antibodies. They found that introducing the bacteria was just as effective as treating them with anti-PD-L1 antibodies, resulting in significantly slower tumor growth. Combining the benefits associated with the bacteria with anti-PD-L1 treatment dramatically improved tumor control.

So they began searching for the specific bacteria that made the difference. They identified microbes from the digestive tracts of JAX and TAC mice by large-scale sequencing. Although there were significant differences in 254 taxonomic families of bacteria from the 2 sets of mice, 3 groups were prominent.

When they tested the effects of each group on the mice’s immune systems, 1 group, the Bifidobacterium, stood out. Within 2 weeks of oral administration, TAC mice that received just Bifidobacterium species had a marked increase in the antitumor T cell responses.

A second study, from the Institut Gustave Roussy in Paris, France, published in the same issue of Science (10.1126/science.aad1329), found that antibiotics could disrupt the antitumor effects of ipilimumab. Replenishing lost microbes in germ-free and antibiotic-treated mice restored the drug’s anti-cancer effects.