New Research Sheds Light on Hot and Cold Tumors

Ben Stanger, M.D., Ph.D., Perelman School of Medicine, University of Pennsylvania

The biggest buzz in cancer treatment during the past several years is immunotherapy.

Some patients with solid tumors like melanoma and lung cancer, for example, have not only had their lives extended, but in some cases have been cured. For years, the general consensus was that these tumors respond better to immunotherapy because they have high levels of T cells, the body’s natural defense against invaders, which makes them more sensitive to immune treatments. Researchers dub these tumors as being “hot.” Unfortunately, pancreatic cancers have not responded well to immunotherapy efforts. And one potential reason why is that these tumors are often “cold,” meaning they have fewer T cells.

But researchers have been trying to figure out if this is indeed the case. Are the levels of T cells contained in a tumor actually the only reason why immunotherapy may or may not work? Or is there something more going on?

Now a team from Perelman School of Medicine’s Abramson Cancer Center (University of Pennsylvania, Philadelphia) has shed some light on that question. They have discovered that whether a tumor is hot or cold and how that tumor responds to treatment are actually determined by information embedded within its cancer cells.

“Twenty-five years ago the whole field of immunotherapy was a backwater of cancer research, and now it’s the most exciting thing that you can think of, but it takes time to figure out the details on how to make it work,” explains Dr. Ben Z. Stanger, the senior author of the paper published in the journal Immunity and a professor of gastroenterology and cell and developmental biology at Penn Medicine.

How the Team Worked Out the Details

Pancreatic cancer is resistant to treatment for many reasons. One reason is that these tumors are considered “heterogeneous.” Tumor heterogeneity simply means that one person’s pancreatic tumor is different from another’s pancreatic tumor. Take it one step further and pancreatic tumors, depending on the individual, may actually be “hot” or “cold.” That also can influence how a tumor may respond to immunotherapy, says Stanger, director of the Abramson Cancer Center’s Pancreatic Cancer Research Center. “But we wanted to see how a pancreatic tumor became hot or cold in the first place.”

The first step was to look at tumor heterogeneity and the many differing ways that these cells grow, spread, respond to treatment, and exhibit their diverse natures. To that end, the team harvested pancreatic tumor cells from various mouse tumors. They then created what are called cell clones of these individual tumors by implanting them in healthy mice with normal immune systems. “Basically we allowed heterogeneity to arise naturally in the mice so that we could understand how differences come about and the implications for therapy,” Stanger says.

What they found is that some of those tumors were “hot,” containing many T cells, but the majority were “cold,” containing fewer T cells. And whether a tumor was hot or cold determined if it would respond to immunotherapy. In fact, more than half the mice with hot tumors experienced tumor regressions after treatment with chemotherapy and immunotherapy drugs. This combination included checkpoint inhibitors (a checkpoint inhibitor is a type of drug used in immunotherapy treatment that is often made of antibodies), which unleash an immune system attack on cancer cells. The checkpoint drug’s effect was made more powerful by adding an anti-CD40 agonist (an agonist like this activates the immune system to start an immune response).

The mice with hot tumors that were treated with this combination of chemotherapy and immunotherapy had a durable response to therapy, surviving for more than six months. But none of the mice with cold tumors showed the same response to this regimen.

The researchers wanted to find out why. In other words, what was the molecular basis of this finding?

How a Pancreatic Tumor Is “Wired” Makes a Difference

It seems that as tumors grow, they develop two different ways to avoid an attack by the immune system’s T cells, which recognize specific things like proteins from a virus or proteins from a cancer cell (often called “antigens”). “One trivial explanation is tumors with lots of T cells may have more antigens, and that’s one of the big thoughts behind melanoma, which has a lot of mutations and lots of potential antigens that can be recognized by the immune system,” Stanger explains. But cold and hot pancreatic tumors actually seem to have a comparable number of mutations, and whether you have a robust immune system prepared to fight cancer is not dependent on how many mutations a tumor has, he adds.

So what makes the difference? The team found that the “cold” pancreatic tumor actually makes a signaling protein called CXCL1 that recruits another type of immune cell called a myeloid cell. These myeloid cells are immunosuppressive—meaning they enter the tumor and prevent the T cells that are available from attacking.

“Essentially, the way the (pancreatic) tumor is wired will determine whether it will bring in myeloid cells or not, and if it brings in those myeloid cells, it won’t be sensitive to immunotherapy,” Stanger says. He adds that knocking out CXCL1 in cold tumors allowed T cells to infiltrate the tumor, making it more sensitive to immunotherapy.

Applying the Finding to Immunotherapy Treatments

Although this finding currently does not directly translate into patient treatment, this kind of preclinical work is what helps the field move forward in pancreatic cancer immunotherapy treatment. “We needed to find out the details—the ‘why,’—one of the reasons why immunotherapy isn’t that effective with pancreatic cancer,” Stanger says, adding that even with hot tumors, it’s necessary to add treatment to keep the tumor from growing unchecked.

Stanger is very optimistic about the future of immunotherapy and pancreatic cancer. “Yes, I’m optimistic and I know others are too, because the more detailed information we get about pancreatic cancer, and how the underlying biology of tumor cells can affect immunotherapy treatment, the closer we get to making it potentially more effective,” he says.

He cites the multi-center Parker Institute trial (see the story “Collaborative Multi-Center Immunotherapy Trial Targets CD40 and PD-1”), led by the Abramson Cancer Center, as an example of the field moving in a positive direction regarding immunotherapy. The Parker Institute trial is examining the combination of standard chemotherapy and two immunotherapy agents: an anti-PD-1 checkpoint inhibitor and a novel antibody targeting CD40, a protein that when activated can drive the immune system to attack tumors—a combination similar to the one used in Stanger’s study.

“There are a lot of very dedicated people working out the details, and every discovery we make answers some questions, and sometimes brings up even more,” Stanger says. “But everyone’s goal is the same and that’s to successfully treat more patients. And there’s no doubt that we will get there.”