Dr. Gajewski’s laboratory studies the regulation of T lymphocyte activation, differentiation, and negative regulation, and applies this knowledge toward understanding anti-tumor immunity in vivo. Key concepts are moved forward into translational clinical trials in patients with melanoma and other cancer types. One key positive regulator of anti-tumor T cell responses is the cytokine IL-12, which has been integrated into phase I and phase II clinical trials in combination with melanoma vaccines. Recent observations have revealed that even if anti-tumor T cells are properly activated and home to tumor sites, that negative regulatory mechanisms may dominate within the tumor microenvironment. These include T cell anergy, inhibition by CD4⁺CD25⁺ regulatory T cells, engagement of the inhibitory receptor PD-1 by PD-L1, and tryptophan catabolism by indoleamine-2,3-dioxygenase. Current translational efforts are aiming to block these inhibitory pathways to augment the effector phase of anti-tumor immune responses. In addition, his laboratory has characterized defective Ras-based signaling in anergic T cells, and is dissecting the regulation of Ras activation as a potential therapeutic target for immunopotentiation.