When we think of a tumor, we tend to think of the cancerous cells themselves, rogue agents fueled by a mindless collection of mutations that spur uncontrolled growth and division.
But cancer is not just the cancer itself. It turns out that the tumor’s neighbors can be just as important to the disease.
Like tiny con men, cancer cells are adept at tricking healthy parts of the body into doing their dirty work for them. Some tumors build physical walls around themselves by recruiting healthy cells or molecules to do their bidding. Many can trigger the growth of new blood vessels to supply them with energy for their expansion. In some cancers, like certain lung cancers, tumors can actually contain more noncancerous cells than cancer cells.
This “tumor microenvironment” — the noncancerous cells and molecules that are nevertheless an integral part of cancer — also heavily influences whether a treatment will work. Especially, researchers are finding, in the case of immunotherapies.
When it comes to this burgeoning class of cancer treatments that harness the body’s own immune system to attack tumor cells, the microenvironment is king. In fact, some recently developed cancer immunotherapies ignore the cancerous cells entirely, focusing instead on enabling neighboring healthy cells to slip out of the tumors’ grasp and realize their natural cancer-killing abilities. The tumor’s local milieu is so complex, however, it remains a major roadblock standing in the way of applying immunotherapies’ early successes in blood cancers to solid tumors like breast, lung, colon, liver and pancreatic cancers, which are the top five deadliest cancers in the U.S., according to the American Cancer Society.
“Tumor microenvironment issues come hand-in-hand with working on solid tumors,” said Fred Hutchinson Cancer Research Center’s Dr. Kristin Anderson, who is part of a team working to develop immunotherapies for ovarian cancer and other solid tumors.
That’s why cancer researchers need to understand it.
One of immunotherapy’s biggest success stories to date — a class of drugs known as checkpoint inhibitors, the first of which gained Food and Drug Administration approval in 2011 — owes its existence to the tumor microenvironment. One such drug, pembrolizumab (perhaps best known for sending former President Jimmy Carter’s advanced melanoma into remission), works by reinvigorating T cells in and around tumors. Some T cells, a type of immune cell, have the potential to recognize and eliminate cancer cells, but the tumors fool the T cells into ignoring them by triggering a particular molecular switch, said Fred Hutch immunologist Dr. Robert Pierce.
The cancer cells or other cells tumors recruit to their microenvironment “reach over and hit the snooze button on the T cell,” Pierce said. “The T cell sits there asleep — like sleeping beauty.”
Pembrolizumab and other checkpoint inhibitors in its class work by blocking the T cells’ molecular snooze button, “then they wake up and start killing the tumor,” Pierce said. Before joining the Hutch, Pierce worked at Merck, the pharmaceutical company that developed pembrolizumab, as part of a biomarker-development team, and he led the early efforts to test the drug in the rare skin cancer Merkel cell carcinoma and in a type of lymphoma.
But the drugs don’t work for everyone, Pierce said. Even in disease types where some patients are seeing dramatic responses — like lung cancer and Merkel cell carcinoma — tumors in many or even most patients treated with checkpoint inhibitors do not shrink.
For example, in non-small cell lung cancer, by far the most common type of lung cancer, only 20 percent of patients respond to existing checkpoint inhibitors, said lung cancer researcher Dr. Julia Kargl. But researchers don’t fully understand what separates those patients from the 80 percent who don’t benefit.
Kargl, a former Fred Hutch postdoctoral fellow who recently established her own lab at the Medical University of Graz in Austria, wanted to help answer that question. She and her colleagues in Dr. McGarry Houghton’s laboratory at the Hutch had reason to believe the types of immune cells in the tumor microenvironment could be part of the reason.
Time is of the essence for better understanding the cellular makeup of solid tumors, Kargl said. Besides the handful of checkpoint inhibitors already on the market, there are many more checkpoint inhibitors and other related therapies in development in labs and in clinical trials around the world. As more and more new cancer treatments come on the scene, somebody will need to figure out which patients are most likely to respond to which drugs.
“We are hoping that if we know which immune cells are present in the tumor, we could better identify patients that can benefit from immunotherapy,” Kargl said. “We will need good criteria to select which drugs or which drug combination is beneficial for patients.”
In a study published earlier this year in the journal Nature Communications, Kargl, Houghton and their colleagues did a deep dive into the immune cells present in biopsies taken from 73 patients with non-small cell lung cancer. The team looked at 40 different types of immune cells in each of those samples — and from all that data, a few highlights stood out. For one, these tumors contained a lot of noncancerous cells, Kargl said. More than 65 percent of the “tumor” sample was actually made up of immune cells.
“When we think about a tumor, we usually think about the accumulation of tumor cells,” she said. “But when we look at these tumors, we have these islands of tumor cells and they are surrounded by immune cells. So there’s a really strong immune reaction to the tumor, but the reaction just hasn’t been the right one to kill the tumor cells.”
Those pools of immune cells in lung cancer mainly include one type of cell: neutrophils, typically the immune system’s first responder to infections or injuries. Normally, neutrophils live only six hours, but the lung tumors have figured out tricks to both keep the immune cells alive longer and to continually attract a new supply of neutrophils to the neighborhood. The tumors coerce the neutrophils to form living moats around the cancerous islands that other immune cells, like cancer-killing T cells, may not be able to bridge.
Past research has shown that patients with fewer T cells present in their tumors tend to fare worse overall — and are less likely to benefit from checkpoint inhibitors. If there are few T cells present in the tumor, there may be no cancer-killing cells around for drugs like pembrolizumab to “wake up.” But it’s not entirely clear why some tumors have plenty of T cells on board and some don’t. In their recent study, Kargl and her colleagues saw that lung tumors with more neutrophils had fewer T cells, and vice versa.
It’s not clear from their study what the neutrophils are doing in the tumors, Kargl said, and they don’t have biopsies from patients who have received checkpoint inhibitors — the biopsies were all taken from patients while they were undergoing surgery to remove their tumors before they’d received any other treatments. But their theory is that if these neutrophils are actively keeping helpful immune cells out of the tumor, a treatment that killed off or otherwise blocked the neutrophils could allow T cells in — and could allow more patients to benefit from checkpoint inhibitors. The research team is currently conducting preliminary experiments in a mouse model of lung cancer to test the idea.
The microenvironment also plays a big role when it comes to the success or failure of T-cell therapy, which relies on T cells that are put into the patient’s bloodstream to seek out the tumor rather than T cells that are already inside the tumor. This form of immunotherapy is showing early promise in certain blood cancers, but researchers are still working to translate that promise for most solid tumors. T-cell therapy most often entails extracting a patient’s own T cells from their blood, engineering the cells with new cancer-killing abilities in the laboratory, and multiplying them many times before they are infused back into the patient’s bloodstream.
Anderson, a postdoctoral fellow working with Fred Hutch immunotherapy researcher Dr. Phil Greenberg, recently led a study that underscored the importance of the tumor microenvironment in developing these immunotherapies for ovarian cancer. Anderson and colleagues found that engineered T cells can kill cancer cells, which leads to extended survival in a mouse model of cancer. But the therapy is not ready for testing in humans yet, she said. The research, which Anderson presented in April at the annual meeting of the American Association of Cancer Research in Washington, D.C., also identified several roadblocks to achieving an effective ovarian cancer T-cell therapy that can eradicate the tumor, many of them related to the tumor microenvironment.
The team uncovered six separate ways ovarian tumors foil the attempts of engineered T cells to kill them. But the good news is that researchers may not need to solve all six problems to help more patients benefit from immunotherapy, Anderson said. Removing one or two of these roadblocks could boost the effects of T-cell therapy enough to overcome ovarian and other solid tumors.
Their first step will be to circumvent the molecular “snooze button” that — as with naturally occurring T cells — can put engineered T cells to sleep. Existing checkpoint inhibitor drugs could work, Anderson said, but researchers in the Greenberg Lab are also exploring whether they can engineer the T cells to stay awake at the same time that they’re engineering the cells with enhanced cancer-killing abilities.
The team is also working on two other forms of T-cell engineering to make the cells even more resistant to the tumors’ tricks. Anderson and her colleagues found that ovarian cancer cells — and the blood vessels around them — send “death signals” that cause T cells making their way to the tumor to self-destruct before they can do their jobs. Dr. Shannon Oda, another researcher in the Greenberg Lab, is working to change how engineered T cells receive that death signal, and then rewiring their internal circuitry to not only stay alive but actually increase their anti-tumor activity in response.
Other researchers in their lab are working on ways to allow T cells to process alternate forms of energy. T cells and cancer cells compete for limited glucose in their surroundings as an energy source, and the cancer cells often win. If T cells had a different fuel source, they might thrive in the hostile microenvironment even longer.
Although Anderson’s current work focuses on ovarian cancer, a particularly deadly and difficult-to-treat cancer, she hopes the roadblocks her team has identified — and the eventual routes around them — could apply to other cancers, too.
“If we can solve some of the issues that really plague us with these hard ones, then we can more readily apply [the solutions] to cancers that have fewer of these hurdles,” she said.
Rachel Tompa is a former staff writer at Fred Hutchinson Cancer Center. She has a Ph.D. in molecular biology from the University of California, San Francisco and a certificate in science writing from the University of California, Santa Cruz. Follow her on Twitter @Rachel_Tompa.