Using genetically engineered mouse models of cutaneous carcinogenesis to characterize oncogene-driven cancer immunoediting

Abstract

Cancer develops as the end product of a multistep process in which cells and/or their microenvironments accumulate alterations, either genetic or epigenetic, which enable uncontrolled growth. During the early steps of this process, altered cells constituting the precursors to cancer are subject to the constraints of natural selection. As such, variations within the population of transformed cells which lead to increased relative fitness are reproductively favored by the various selective pressures of the local microenvironment. Anti-tumor immunity is an important arm of this pre-malignant niche. Consequently, for cancer to develop, at least one of the following four possibilities must occur: 1) the transformed cells progress to cancer without ever becoming immunogenic, 2) the transformed cells are immunogenic, but are able to proliferate faster than they are eliminated, 3) the host immune system becomes compromised or tolerized, or 4) from within the transformed population, new clones evolve adaptations that enable evasion of anti-tumor immunity. This final possibility has been termed “cancer immunoediting” and it includes three distinct stages of cancer-immune interaction: elimination, equilibrium, and escape. As a result of this process, every immunogenic cancer that develops in an immunocompetent host is intrinsically immune-evasive as a result of its past triumphs over anti-tumor immunity. Here, I describe a genetically engineered mouse model developed in order to study this process directly, via in vivo confocal microscopy. This model accurately recapitulates the cancer immunoediting process which occurs as a result of common mutations that drive human carcinomas. Using this model, I identified a previously unknown mechanism of early survival in which transformed cells use an immune-privileged niche as a surrogate for immune evasion. This project also provides a means to further characterize the adaptations that mediate the transitions between the stages of immunoediting. Finally, and perhaps most importantly, this model acts as a prototype for discovery of new biomarkers of human immunoediting as well as a screening tool for therapeutic interventions that could form the basis of rational cancer prevention strategies.