page 4). Thus, Gajewski and his teamed originally hypothesized that the presence of these immune-suppressing mechanisms would make patients less responsive to vaccine therapies. However, the exact opposite turned out to be true. The patients with tumors containing these T-cell-­ inflamed tumor microenvironments had a better clinical response. Because IDO, PD-L1 and Foxp3+ are associated with the presence of CD8+ T cells in the tumor microenvironment, their presence actually predicts response to vaccines. “More importantly, this suggested that IDO, PD-L1, and Tregs might be targets for new therapy devel- opment—eliminating these inhibitory pathways could be therapeutic,” Gajewski said. PIONEERING NEW TREATMENTS Checkpoint inhibitor immunotherapies help the immune system mount an attack by deactivating specific proteins or molecules that control immune checkpoints, which cancer cells use to avoid detection. PD-L1 is one such checkpoint target, along with programmed cell death protein 1 (PD-1), which is the protein PD-L1 binds to. PD-L1 and PD-1 are found on the surface of both normal and cancer cells, and help prevent the immune system from running rampant by limiting T-cell overactivation. However, this can hinder the body’s ability to fight cancer. Inhibitor drugs “turn off” these otherwise well-meaning proteins and molecules so the body can mount a robust immune response. Multiple clinical trials at the University of Chicago Medicine are testing combination therapies of PD-1 or PD-L1 inhibitors with other checkpoint inhibitors in various tumor types, including melanoma, bladder cancer, ovarian cancer, and triple-negative breast cancer, to name a few. Immunotherapy and the Microbiome A team of researchers led by Thomas Gajewski, MD, PhD, professor of medicine and pathology, and including Comprehensive Cancer Center faculty Eugene Chang, MD, Martin Boyer Professor of Med- icine, Bana Jabri, MD, PhD, professor of medicine, and Marisa Alegre, MD, PhD, professor of medicine, have shown that a person’s gut bacteria (microbi- ome) may play a role in patient response ­ to immunotherapies. By introducing a particular strain of bacteria called Bifidobacterium into the digestive tracts of mice with melanoma, Gajewski and colleagues were able to boost the ability of the animals’ immune systems to attack tumor cells. The combination of oral doses of the bacteria and injections with a check- point inhibitor immunotherapy, called anti-PD-L1 antibody, nearly abolished tumor outgrowth. “The field has recently recognized close connec- tions between the gut microbiome and the immune system,” Gajewski said. “This finding provides a novel way to exploit that connection, to improve immunotherapy by selectively modulating intesti- nal bacteria.” The study1 garnered attention in the research community, and Gajewski has teamed up with Evelo Biosciences to develop a microbiome-based cancer therapy and clinical trial. 1 Sivan, et al., Science 350:1084-1089, 2015. Thomas Gajewski, MD, PhD, with a patient 2 PATHWAYS TO DISCOVERY SPRING 2017