To Fight Cancer, We Must Fight Ourselves

A depiction of cellsThis article, written by Jason Bittel, originally appeared in the winter 2019/20 issue of Pitt Med magazine.

People often think about cancer as though it’s a foreign assault on the body. An alien growth. An invader that needs to be repelled. 

But this is all wrong, says Dario Vignali, vice chair and professor of immunology at the University of Pittsburgh. 

“The challenge is because it’s not foreign. It’s part of us,” says Vignali, who is also coleader of the cancer immunology program and codirector of the Tumor Microenvironment Center at the UPMC Hillman Cancer Center. “It’s transformed us, but it’s, nonetheless, still us.” 

Interestingly, this is what can make cancer so difficult to combat. Tumors don’t have a brain, says Vignali, but they do seem to know how our immune system works, and they use that knowledge to slip under the radar, short-circuit our defenses, and even co-opt the cells that should be fighting against them to do their bidding.

In 2019, Vignali and his team published two papers that explain some of the many ways tumors do what they do. But to understand them, you need to first understand a bit about how the immune system functions.

“We all know that one of the major cell types that can destroy cancer is called a cytotoxic T cell,” says Vignali. 

Also commonly referred to as CD8+ T cells, these battle-bots rove around in our blood looking for things they don’t like. When they find a target, such as a cell that’s become infected with a virus, it’s the CD8+s’ job to annihilate it. Cancer cells can also draw the attention of CD8+s; however, the defender’s search-and-destroy response doesn’t always go as planned. Often, the CD8+s come screaming into the area, ready for a fight, only to power down like they’ve been hit with a tranquilizer dart. 

Why? Well, it turns out that there’s another type of T cell known as the regulatory T cell, or Tregs, whose job it is to make sure the CD8+s don’t get carried away and start attacking things that don’t need to be attacked. “Tregs are like the conductor of an immunological orchestra,” says Vignali. “They are critical for ensuring that the immune system behaves itself. That it doesn’t go too wild; that the parties aren’t too festive.” This helps limit unnecessary tissue damage that leads to autoimmunity or inflammation. 

Scientists have long known that tumors tend to attract Tregs, which cause all the CD8+s that could be fighting the cancer to sort of go to sleep. But what’s been missing is exactly how these cells communicate. That is, how does one kind of T cell make another kind of T cell turn off? 

It’s kind of like getting a car. It looks great, but you don’t really know how it works. So if it breaks down, you can’t fix it. First we need to understand how it works. Then we can fix it.

Dario Vignali

According to Vignali’s April study, published in Nature Immunology, it all comes down to a couple of messenger molecules known as inhibitory cytokines—specifically, cytokines known as IL-10 and IL-35. What’s more, Vignali has shown that if you take away the Tregs’ ability to produce those inhibitory cytokines, as he’s done in experiments with mice, then the CD8+s can successfully eradicate the tumor. 

In other words, we may be able to help our own bodies fight cancer by inhibiting the inhibitors. 

Of course, there’s more than one way to skin a Treg. And in another new study, this one published in Immunity, Vignali’s team showed that a similar effect can be achieved by targeting a protein called neuropilin-1. 

Neuropilin-1 “plays a key role in stabilizing regulatory T cells in this very hostile tumor environment,” says Vignali. “So we discovered that if we target neuropilin-1, by genetically removing it from a Treg or blocking it with an antibody, now the Tregs collapse, and they don’t work anymore.” 

And once the Tregs are down, the cytotoxic T cells can get back to work giving the cancer cells the boot. 

All in all, if we’re going to beat cancer, then we’ve got to get to know our own immune systems at least as well as cancer does. 

“It’s kind of like getting a car,” says Vignali. “It looks great, but you don’t really know how it works. So if it breaks down, you can’t fix it.

“First we need to understand how it works. Then we can fix it.”

Read more articles from Pitt Med Magazine's winter 2019/20 issue