To Fight Cancer, We Must Fight Ourselves

The immune system often stops itself from destroying cancer cells
Winter 2019
Invasive ductal carcinoma (pink and purple) of the breast shows infiltration by various immune cells: CD8+ T cells (orange),  B cells (cyan), and CD4+ T cells (green). Nuclei are blue.
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 damned 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? 
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.”


Image Courtesy Sayali Onkar. 

There may be molecular switches that control life span and health span separately in the worm C. elegans.

Nitty Gritty

This just in re life span and health span


How organisms manage to age well is not a question with straightforward answers.
In a surprising paper recently published in Nature Communications, Pitt researchers contribute to science’s understanding of what promotes health span—the health and quality of life—which may be a better measure of aging than life span.
The team was led by Arjumand Ghazi, associate professor of pediatrics, developmental biology, and cell biology at Pitt. It all started when Ghazi was exploring the impact of the protein TCER-1 in the worm Caenorhabditis elegans. A long-standing dogma in the aging field has been that longevity and stress resistance go hand in hand, and genes that promote longevity often also support grit in the face of stress. 
Ghazi’s team expected the mutants lacking TCER-1 would be highly vulnerable. But when exposed to stressors—like extreme temperatures, harmful chemicals, or hostile pathogens—the worms without the protein were actually more resistant.
“It took us a long time to believe it,” Ghazi says. In fact, they ran the experiments some 10 times over the next three years to confirm these confounding findings. (In her lab, experiments are usually run at least three times.)
Interestingly, the researchers observed, the mutants lacking TCER-1 only showed enhanced protection against pathogens when the animal was fertile. 
Why would this happen? Previously, Ghazi’s lab had reported that TCER-1 promoted both longevity and fertility; perhaps the worms were diverting resources in fertility’s favor at the expense of immunity, the team posited. They were allocating resources.
The team then tried boosting TCER-1 levels in a group of worms and found that fertility loss was less drastic in the presence of a pathogen. In contrast, in the control group—normal animals under the threat of infection—fertility took a big hit. 
Ghazi speculates: “If everything is good, high levels of TCER-1 make an animal live longer and reproduce more.” However, there’s a price: When these worms get exposed to pathogens, they’re not able to survive.
In addition to being more resilient, the worms without TCER-1 also showed improved mobility later in life. Named for its elegant movements, C. elegans is barely able to move by day 13 of its two-week life span. The mutant worms, however, were visibly spryer.
These findings bolster health span as a key part of understanding how organisms age. How long animals live is not, in itself, a good way to get a handle on the genes affecting the quality of their lives, Ghazi says.
Just as one 80-year-old human might be in a nursing home while another is out running marathons, she adds, the quality and health of life are of critical importance. Measuring health span is as challenging in worms as it is in humans, but in that challenge lie opportunities to understand the aging process more deeply.
Next, Ghazi hopes to test these findings in mice. Although she cautions against drawing parallels between worms and humans, the paper points toward exciting possibilities, like extending or preserving a woman’s fertility or perhaps flipping a genetic “switch” to reallocate resources from fertility to immunity.
“This research makes a strong case for looking at whether higher organisms do the same thing,” Ghazi says. “If that is the case, you can imagine manipulating it to affect the aging system, the reproductive system, the immune system.”
Image reprinted with typographic alterations from Nature Communications, Article number: 3042, Francis R. G. Amrit et al, under Creative Commons CC BY License © 2019.

The hearts of two mouse embryos share the same mutation. The one on the right was subject to correction of a gene in the placenta, and only in the placenta, demonstrating that the defect on the left is entirely the result of placental malfunction.


Placenta health linked to fetal heart defects

By Kristin Bundy 

In 1999, Yaacov Barak detailed findings in Molecular Cell suggesting a wholly new paradigm: a mechanistic connection between a placental defect and fetal abnormalities of the heart. “There was a lot of study into the causes of these heart defects,” says the associate professor of obstetrics, gynecology, and reproductive sciences at the University of Pittsburgh. “But they all focused on the heart.”
Barak stumbled upon this connection while studying the function of a gene known as PPARγ and its impact on fat cells. He performed a “knockout” experiment, in which the gene was disrupted in mouse embryos. The researchers hypothesized that without PPARγ—which encodes a protein considered the master regulator of fat cell differentiation—fat cells would fail to form. 
Instead, they found that all of the embryos without PPARγ died early on because of placental defects. “And PPARγ is expressed nowhere else at the time of death except the placenta.” On top of that, they found heart defects in the embryos, but no evidence that PPARγ was expressed in the heart.
They decided it must be that whatever PPARγ does in the placenta must affect the heart—and the data suggested as much. When they corrected PPARγ in the placenta, the fetal heart went back to normal.
Given that about one in 140 babies is born with congenital heart disease and must undergo surgery or endure frequent monitoring, you might anticipate that the news of this possible new therapeutic target was well received, especially by pediatric cardiologists.
But the biomedical community flat-out rejected the idea. It was an unambiguous experiment, says Barak, and still, “People said there must be an error they couldn’t put their finger on, or the results were just an anecdotal novelty.” Colleagues and grant reviewers called him delusional. 
Barak, who came to Magee-Womens Research Institute in 2008, shelved the finding for years, focusing instead on placental development, fat cells, and PPARγ target genes.
Then, five years ago, he began to see his ideas crop up in the literature in epidemiologic studies. “Funny thing is, people didn’t remember where they heard the idea. We weren’t even cited,” he says. “Somehow what I did 20 years ago sank into the collective lore and remained because they knew something was there.”
In 2018, he applied for the Magee Prize, a $1 million grant for novel and out-of-left-field ideas to advance scientific discovery in women’s health. Competing against 26 other teams, Barak found his peers receptive this time, and won. The award was presented at the Magee-Womens Research Summit in October 2018.
With the award, he is currently collaborating with two researchers—Myriam Hemberger, an expert in placental development at the University of Calgary, and Henry Sucov, a heart expert of the Medical University of South Carolina. Their focus is to generate more precise mouse models, which, thereafter, they will use to interrogate the connection between the placenta and heart. “We’re doing this through different types of omics—mainly gene expression—as well as screens for potential hormones that might mediate the effect,” says Barak.
He also studies other unorthodox mechanisms. One that has caught his attention of late is how fat cells die. This is an offbeat approach, he says. “No one is studying it, and I think it’s one of the keys for understanding and treating type 2 diabetes.” He concedes such ideas might fall on deaf ears.
At least, at first.
Image courtesy Yaacov Barak