mount a defense—is the Stimulator of Interferon Genes (STING) protein. In 2014, Gajewski and colleagues found that the STING pathway triggers a natural immune response against tumor cells and helps jump start the production of CD8+ T cells. This observation generated the idea that pharma- cologic stimulation of STING could prove useful for patients with non-T-cell-inflamed tumor micro- environments, or “cold” tumors, who normally don’t have a robust response to immunotherapy. This proved to be the case, and STING agonists (chemicals that stimulate a biological response) were found to have profound therapeutic activity in mouse models of cancer. Justin Kline, MD, assistant professor of medicine, and Emily Curran, MD, clinical instructor of med- icine, are studying the STING pathway in acute myeloid leukemia (AML). Using mouse models, they were able to stimulate STING by injecting substances that mimic tumor-cell DNA into the bloodstream. “Delivery of these substances into the blood led to massive immune responses,” said Kline. “I’ve worked extensively with animal models of this disease, and have never seen responses like this.” Based on this work and a licensing arrangement with Aduro Biotech, University of Chicago researchers are conducting clinical trials testing the first STING agonist in melanoma, head and neck cancer, and triple-negative breast cancer. THE FUTURE OF IMMUNOTHERAPY New and promising types of immunotherapy have emerged in the past five years. For example, CAR T-cell therapy for acute lymphoblastic leukemia (ALL) and other blood cancers involves engineer- ing a person’s own immune cells to recognize and destroy cancer cells. Understanding the Life Cycle and Lifestyle of Tregs Peter Savage, PhD, associate 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 Comprehen- sive Cancer Center with Gajewski. “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.” A major step, he said, is understanding what other cells they interact with—what Savage calls the “dance partners” of Treg cells. “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 addressing this very puzzle. How can scientists target Treg cells in one part of the body, like a tumor, without creat- ing disorder in the rest of the body? Disrupt- ing 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. Peter Savage, PhD, in his lab 4 PATHWAYS TO DISCOVERY SPRING 2017