THE IMMUNOTHERAPY REVOLUTION In the past decade, immunotherapies have revolutionized the way we treat cancer. By activating the immune system, these powerful treatments are able to use the body’s own defense mechanisms to attack cancer cells and halt tumor growth. Scientists at the University of Chicago Medicine Comprehensive Cancer Center are leading the field of immunology, from basic research that aims to understand how the immune system works at the molecular level to clinical trials that are testing the newest and most promising therapies. However, immunotherapy is not always effective. No two cancers are alike, and genetic, biological and environmental factors can make some people less likely to respond to immunotherapy. So, how do you overcome this barrier and develop better therapies that can help more patients? UNDERSTANDING PATIENT RESPONSE TO IMMUNOTHERAPY Our researchers have uncovered several fac- tors that play a role in a patient’s response to immunotherapy. For example, Thomas Gajewski, MD, PhD, professor of pathology and medicine, recently found that a person’s gut bacteria, or microbiota, may impact the effectiveness of cer- tain immunotherapies (see sidebar on page 2). Another key player is the tumor microenviron- ment—the cellular environment in which a tumor lives. The microenvironment consists of tissue, blood vessels, immune cells, fibroblasts, and other components that interact with the tumor cells. As it turns out, the tumor’s “home” plays an important role in how tumors behave and their susceptibility to certain drugs. Gajewski coined the term “T-cell-inflamed tumor microenvironment” to describe a major subset of tumors from patients whose cellular environments harbor qualities that make them more likely to respond to immunotherapies.1 More than two decades ago, researchers began testing cancer vaccines that aimed to elevate a person’s level of antigen-specific T cells—white blood cells that can recognize antigens, or short protein fragments, displayed on the surface of cancer cells. The scientists observed that some people already had elevated levels of T cells in their blood prior to vaccination, and the vaccine was ineffective at sparking a response in others. Gajewski’s team set out to decode this dilemma more than a decade ago.2 Gajewski and his team analyzed tumor tissue samples from patients with metastatic melanoma, and found that certain tumor microenvironments contain cytotoxic (CD8+ ) T cells, a type of white blood cell that can recognize and kill cancer cells. They also identified the presence of inoleamine-2, 3-dioxygenase (IDO), programmed death-ligand 1 (PD-L1), and Foxp3+ regulatory T (Treg) cells, which are all inhibitory mechanisms that can restrict the function of tumor-specific CD8+ T cells.3 The IDO enzyme, PD-L1 molecule, and Foxp3+ Treg cells all play a role in regulating the immune system by keeping T cells in check (see sidebar on CANCER.UCHICAGO.EDU 1