Understanding the life cycle and lifestyle of regulatory cells key to cancer immunotherapies
Immunotherapies are changing the way we treat cancers. These promising and potent drugs aim to harness the body's immune system, directing it to attack tumors and halt metastasis. But, it isn't as simple as a single command. Our immune system operates through a complex network of cells that communicate and interact in ways we don't fully understand. Much of the research being conducted in immunotherapy is focused on this very question what cells are the key players in the immune response and how do they develop and interact with other cells in their environment?
We already know that T cells, a type of white blood cell, act as the immune system's army, fighting off infections and viruses. Today, scientists are aiming to understand the role different subtypes of T cells play in immunity.
Peter Savage, PhD, assistant professor of pathology, and his colleagues are studying Foxp3+ regulatory T (Treg) cells, a unique type of T cell that does not participate in host defense against pathogens and tumors. Instead, Treg cells actually suppress immunity by regulating other T cells.
"Treg cells are the peacekeeper cells that suppress unruly immune responses," said Savage, who co-leads the Immunology and Cancer scientific program at the University of Chicago Medicine Comprehensive Cancer Center. "They are essential for the prevention of autoimmune diseases like diabetes, arthritis and multiple sclerosis. But, they're thought to be a major barrier to immunotherapy and the ability of our immune system to fight cancer."
Sensing conflict in the body, Treg cells are often drawn into tumors, where their peacekeeping abilities limit the ability of the immune system to attack cancerous cells. So, why not just remove the Treg cells so the body can mount a full immune response? Unfortunately, scientists haven't figured out a way to selectively delete all of the Treg cells in a tumor without erasing them from the rest of the body. And, without Treg cells, a person wouldn't be able to live.
Savage and his colleagues are interested in solving this dilemma. "We're trying to understand the basic rules by which Treg cells develop and function. What is their life cycle and what is their lifestyle?" he said. "Then, we can selectively disrupt an aspect of their lifestyle therapeutically."
A major step, he said, is understanding what other cells they interact with what Savage calls the "dance partners" of Treg cells. In a recent paper published in the journal Immunity, Savage and his colleagues found that dendritic cells are a crucial dance partner, playing a key role in the development and activation of Treg cells.
Treg cells develop in the thymus, an immune organ located in front of the heart and behind the sternum. In order to fully evolve, Treg cells need to recognize antigens, which are molecules that trigger activation of immune cells in order to mount an immune response. But Treg cells, like all T cell subtypes, can only recognize antigens that are presented and displayed to them by antigen presenting cells.
Within the thymus, the antigen that Treg cells recognize is produced by epithelial cells called mTECs. Other scientists have theorized that mTECs present antigen directly to Treg cells. But, Savage and his colleagues have now shown that dendritic cells act as a go-between, taking the antigen from the mTECs and displaying them for recognition by Treg cells.
"Treg cells don't just recognize antigen floating around," Savage said. "The antigen is presented to them by a dance partner. And, the identity of that dance partner is going to dictate a lot of what they do."
Using mouse models, Savage and his colleagues found that removing dendritic cells prevented Treg cells from fully developing. The next step is to try this within a tumor to see if it impacts tumor growth and spread.
"The goal is to manipulate Treg cells only in tumors either take away the partners or block the interaction with the partners because we need Treg cells to function properly elsewhere in the body," Savage said. "Using the peacekeeper analogy ask the peacekeepers to temporarily stand down in the tumor while we release this immune attack."
Many emerging immunotherapy studies, Savage said, are interested in this very puzzle. How can scientists target Treg cells in one part of the body, like a tumor, without creating disorder in the rest of the body? Disrupting the cells they interact with may be one solution. By solving this puzzle, scientists may be one step closer to developing targeted and more effective immunotherapies.