Immune escape as a fundamental trait of cancer: focus on IDO.

Immune escape is a critical gateway to malignancy. The emergence of this fundamental trait of cancer represents the defeat of immune surveillance, a potent, multi-armed and essential mode of cancer suppression that may influence the ultimate clinical impact of an early stage tumor. Indeed, immune escape may be a central modifier of clinical outcomes, by affecting tumor dormancy versus progression, licensing invasion and metastasis and impacting therapeutic response. Although relatively little studied until recently, immune suppression and escape in tumors are now hot areas with clinical translation of several new therapeutic agents already under way. The interconnections between signaling pathways that control immune escape and those that control proliferation, senescence, apoptosis, metabolic alterations, angiogenesis, invasion and metastasis remain virtually unexplored, offering rich new areas for investigation. Here, an overview of this area is provided with a focus on the tryptophan catabolic enzyme indoleamine 2,3-dioxygenase (IDO) and its recently discovered relative IDO2 that are implicated in suppressing T-cell immunity in normal and pathological settings including cancer. Emerging evidence suggests that during cancer progression activation of the IDO pathway might act as a preferred nodal modifier pathway for immune escape, for example analogous to the PI3K pathway for survival or the VEGF pathway for angiogenesis. Small molecule inhibitors of IDO and IDO2 heighten chemotherapeutic efficacy in mouse models of cancer in a nontoxic fashion and an initial lead compound entered phase I clinical trials in late 2007. New modalities in this area offer promising ways to broaden the combinatorial attack on advanced cancers, where immune escape mechanisms likely provide pivotal support.