Natural gut flora appears to strengthen the immune system's response to tumors.
Research carried out at the University of Chicago and published recently in Science found that adding certain bacteria into the digestive tracts of mice increased their immune system's ability to attack tumor cells.
The positive effect of the added bacterial flora was similar in strength to those of checkpoint inhibitors, a type of successful anti-tumor drug.
When oral doses of bacteria were given in conjunction with checkpoint inhibitors, tumor outgrowth was almost abolished.
Study Director Dr. Thomas Gajewski said:
"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."
T cells, a type of white blood cell, are central characters in the immune response. They hunt down infected or cancerous cells and destroy them.
Tumor cells, however, can attach to specific T cell receptors, turning them off and rendering them inert.
Checkpoint inhibitors, such as anti-PD-L1 antibodies, block the tumor cell's ability to attach to the T cells. This, in turn, keeps the T cells active and on the hunt for faulty or errant cells.
Although checkpoint inhibitors have proven very successful in treating a number of cancer types, only around 1 in 3 patients have a vigorous response. This has perplexed researchers.
Dr. Gajewski and his team noticed a similar reaction in the mice that they used. Mice bought from the Jackson Laboratory (JAX) showed a much more robust, natural immune response to tumors than mice purchased from Taconic Biosciences (TAC).
This marked difference, however, completely disappeared once the two strains of mice had spent 3 weeks together in the same cage. The research team suspected that the mice might be sharing microbes, giving the TAC mice an enhanced anti-tumor response.
Following their hunch, they transferred JAX fecal matter into the stomachs of TAC mice. The results were as expected. The TAC mice's response to the tumor was now as robust as the JAX mice. The reverse process of transferring TAC feces into JAX mice gave no effect.
To test the strength of the bacterial response, the team compared the effect of bacterial transfer with anti-PD-L1 antibodies (a checkpoint inhibitor). The responses were equivalent, and when the methods were combined, the results were even more positive.
The team's next step was to hunt down the specific bacteria that was mediating the response. After testing the more prominent species of bacteria, one stood out: bifidobacteria.
In the next phase of tests, bifidobacteria was given to TAC mice orally. After just 2 weeks, the mice showed a marked improvement in their spontaneous T cell reaction to the insertion of a tumor.
This response was just as strong as when the fecal matter was transferred wholesale.
Impressively, the positive effects of the bifidobacteria were relatively long lasting. TAC mice exposed to tumors as long as 6 weeks after the bacterial influx still mounted a strong immune response.
Potential mechanism of bifidobacteria
- Bifidobacteria are found in the gut, mouth and vagina
- Oral doses of bifidobacteria can alleviate infant diarrhea
- They ferment sugars to produce lactic acid in our gut.
Bifidobacteria are one of the so-called good bacteria that occupy a healthy gut. They are a natural resident in human intestines and, along with much of the gut flora, aid digestion.
Dr. Gajewski theorizes that the bifidobacteria might trigger the immune response by interacting with roaming dendritic cells.
Dendritic cells play a pivotal role in initiating the T cell immune response. They also produce important chemicals that mediate immune response - such as cytokines and CD40 - and ensure the correct sub-types of T cells are switched on and ready for battle.
Dendritic cells have been referred to as the "conductors of the immune orchestra."
The team suspects that bifidobacteria colonize sections within the intestines. This enables them to interact with the cells, which communicate directly with dendritic cells, which, in turn, activate tumor-killing T cells.
Dr. Gajewski commented:
"The field has recently recognized close connections between the gut microbiome and the immune system. This finding provides a novel way to exploit that connection, to improve immunotherapy by selectively modulating intestinal bacteria."
The authors also note that this is just the first piece in what is bound to be an astoundingly complicated puzzle. Other bacteria (naturally present or otherwise) could be even more beneficial to tumor suppression; some, of course, could have a negative impact.
Dr. Gajewski's team at the University of Chicago are already looking for the next bacterial contenders.