by Katherine J. Wu
figures by Neal Atsuka

Are we flushing the next big cancer treatment down the toilet?

Probably not – but the contents of our feces could very well be influencing how our bodies respond to cancer drugs. As it turns out, everybody poops – and everybody poops more than poop.

I’m talking, of course, about the gut microbiota – the enormous collection of microbial cells that coexists peacefully alongside our human cells in our digestive tract – and one of the main ingredients of feces. These friendly bacteria that live and work within our bodies have already been shown to impact human metabolism and resistance to infectious diseases. Now, scientists have shown that they may have the capacity to influence cancer patients’ response to a common form of cancer treatment called immunotherapy.

Cancer, hiding in plain sight

In recent years, cancer immunotherapy, in which the body’s own immune system is deployed to root out and destroy cancerous cells, has been hailed as a miracle treatment. But doctors soon discovered that not every patient responds the same way to cancer immunotherapy: up to 70% of patients exhibit resistance to these treatments – and it’s still unclear why.

Cancer occurs when the body’s cells acquire mutations to their genetic code that allow them to grow and replicate uncontrollably. This unhampered growth can, at its worst, create a devastating army of insatiable cells that sap resources away from the rest of the body or interfere with our vital organs. But on the outside of this cancerous cloud is a (nearly literal) silver lining. Cancer cells behave abnormally – and accordingly, their surfaces don’t look like those of a typical cell.

Consider the unusual predicament of Bruce Banner. Tick him off, and he turns into an uncontrollable agent of destruction. With those mutant abilities come changes to his physical appearance, though, and to the untrained eye, the Hulk no longer resembles Bruce Banner.

Luckily, this can end up working to our advantage. Our immune systems have developed to identify and fight any foreign cells in our bodies. This includes all the usual suspects: bacteria, viruses, and the like. But this can also include human cells that don’t resemble the rest of the body, such as cancer cells.

In fact, some immune cells are activated to kill anything in their path – unless the cell in question is able to pass a “checkpoint” by proving its integrity (Figure 1A). But when cancer cells Hulk out, their “normal cell” IDs no longer suffice, and they are annihilated on sight (Figure 1B). However, cancer cells have additional tricks up their sleeves to avoid detection. Immune cells then mistakenly leave these abnormal cell unscathed (Figure 1C), and once again, Hulk smash.

Here’s where cancer immunotherapy comes in. Acting on the knowledge that the immune system is already equipped to deal with cancer cells, researchers have developed tools and drugs to both enhance immune function and dampen cancer cell defenses. These drugs can do one of two things: stop cancer cells from sneaking past these checkpoints by “revealing” their true Hulk form, or enhance the ability of killer immune cells to dispatch cancerous growths (Figure 1D).

At first, cancer immunotherapy seemed like the panacea researchers have sought for decades. But it quickly became apparent that immunotherapy works for only a fraction of patients, and rates of resistance do not seem to be going down. To try and explain the variation in response, scientists are exploring the idea that not all immune systems are created equal. It turns out that the immune system must be adequately trained to be effective – and the most important coaches aren’t even human.

Immune cells, licensed (by bacteria) to kill

Even on our loneliest nights, we are not without friends. Every human body is home to about two to five pounds of living microbes – trillions of cells that outnumber our own. In this way, we’re actually more bacterial than human.

The largest and most diverse population of microbes in the human body is contained within the colon. This intestinal collection of thousands of microbial species of different shapes and sizes called the gut microbiota. What’s more, these microbes aren’t just passive residents of our intestines. In fact, we wouldn’t survive without them: the microbes in our gut aid us in functions as crucial as food digestion, brain activity, immune function, and more. And because so many parts of the human body depend on these microbes, the more diverse the species and activities of this population, the better.

That’s all well and good, but how does this relate to cancer? As it turns out, having a healthy gut microbiota is essential for developing a well-functioning immune system – which, in turn, is critical to a positive response to immunotherapy.

At birth, we are colonized by microbes before we even meet our fathers. The gut microbiota develops and matures as we do, training our immune system how to respond appropriately to both familiar (Bruce Banner) and foreign (Hulk) cells along the way. Compounds produced by bacteria in the gut can directly stimulate the activity of immune cells, increasing the body’s sensitivity to infections and other diseases.

But an overactive immune response in the body could also stand to hurt the members of the gut microbiota, whose cells are technically “foreign” compared to the rest of the human body. To combat this, the gut microbiota can also produce an array of chemicals to dampen overenthusiastic immune responses that might negatively affect these friendly bacteria. As an added bonus, this immune quieting also protects us from autoimmunity, a condition in which the immune system inappropriately attacks even the body’s healthy human cells.

And so, the same killer cells that can go on to battle cancer mature alongside these microbes, reading cues from them to learn what sorts of responses are overzealous, underwhelming, or just right (Figure 2). Without a healthy gut microbiota, the immune system would be almost entirely uncalibrated.

What’s more, the more diverse the microbes in your gut, the better you’ll fare on immunotherapy drugs. It appears that there are certain populations of “good bacteria” that seem to positively influence treatment outcomes – and performing a fecal transplant from drug-responsive patients into cancer-stricken mice helps to shrink the mice’s tumors and extend their lifespan. And when scientists test the immune responses of these mice, they find that they are well-trained and robust – exactly the kind capable of destroying cancerous lesions in the body. But when mice instead get fecal transplants from patients who respond poorly to cancer treatments, they fail to control tumor growth and have a comparably weakened immune response. Basically, it seems that having a healthy, diverse gut microbiota can bolster the effects of immunity-boosting drugs.

In fact, scientists have found that having an unhealthy gut microbiota can negatively affect the outcome of cancer treatments outside of immunotherapy, including chemotherapy and radiation. And recent findings have pointed to the idea that poorly calibrated immune cells may be to blame in all these scenarios. People with homogeneous or sparse gut microbiota appear to have an increased susceptibility to colorectal cancer, and mice who are given antibiotics before cancer treatment fare worse than untreated counterparts.

This work could someday have wide-reaching implications for how we manage the varied responses patients have to cancer treatments, above and beyond immunotherapy.

Despite this, we are still a far cry from deploying poop pills in the cancer ward. Scientists are currently attempting to better define what it is that these “good” bacteria are doing to bolster our immune system. Matters are complicated by the fact that, just like there isn’t one catchall cancer treatment, there isn’t one healthy microbiota: what works well for one patient may leave the next worse off.

Only time will tell if fecal transplants will become a therapeutic mainstay. In the meantime, though, we simply have another reason to take care of the trillions of microbes hard at work inside our bodies.

Katherine J. Wu is a fourth-year graduate student in the Biological and Biomedical Sciences PhD program at Harvard University, where she studies the bacterium that causes tuberculosis. She is the current Co-Director of Science in the News.

For more information:

For more on cancer immunotherapy, check out this SITN article and lecture from our archives.

For more on fecal transplants, see this New Yorker piece.

For a news report detailing two recent studies on the effect of the gut microbiota on cancer immunotherapy, see this Science News piece.