Gut bacteria can dramatically amplify cancer immunotherapy

By introducing a particular strain of bacteria into the digestive tracts of mice with melanoma, researchers at the University of Chicago were able to boost the ability of the animal’s immune systems to attack tumour cells. The gains were comparable to treatment with anti-cancer drugs known as checkpoint inhibitors, such as anti-PD-L1 antibodies.

The combination of oral doses of the bacteria and injections with anti-PD-L1 antibody nearly abolished tumor outgrowth, the researchers report online Thursday in the journal Science.

“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.

“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.”

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 three weeks, they found that co-housing “completely abolished the differences in tumour growth,” Gajewski said. This made them suspect that by sharing exposure to various types of bacteria, the TAC mice had acquired microbes from JAX mice that somehow enhanced their immunity to tumours.

They confirmed their suspicion by collecting faecal 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 tumour growth. The reverse process, transferring faecal 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 tumour growth. Combining the benefits associated with the bacteria with anti-PD-L1 treatment dramatically improved tumour 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 two sets of mice, three groups were prominent.

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

Mice treated just with Bifidobacterium, rather than the full faecal transfer, displayed tumour control comparable to those who received the full mixture. The effect was long-lasting. TAC mice exposed to tumours as late as six weeks after the Bifidobacterium transfer were still able to mount a robust immune response.

Additional tests showed that the Bifidobacterium did not leave the intestine. They appeared to trigger the immune response by interacting with roaming dendritic cells. These scavenger cells detect and process potential threats and present them to the T cells. The researchers suspect that Bifidobacterium colonize a compartment in the intestines. This enables them to interact with the cells that interact with dendritic cells, which activate tumour-killing T cells.

A second study—from the Institute Gustave Roussy in Paris, published in the same issue of Science—found that antibiotics could disrupt the anti-tumour effects. Replenishing lost microbes in germ-free and antibiotic-treated mice restored the anti-cancer effects.

Provided by: University of Chicago Medical Center

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