The concept of immune surveillance, whereby effectors of the immune system recognize and eliminate nascent cancer cells, has gained considerable momentum in recent years due to accumulating advances. The most definitive support for this concept is provided by immunocompromised mouse models, which have been shown to be more susceptible to chemical carcinogenesis protocols relative to immunocompetent mice. This suggests that transformed cells are killed by the immune system in immunocompetent mice. Such studies emulate the drastic increase in tumor incidence that is observed in human organ transplant patients who receive immunosuppressant drugs to curb graft rejection. However, immune responses to neoplasms do not always result in elimination and can instead lead to an induced state of tumor dormancy. This concept has been corroborated by a number of striking human cases in which fatal melanomas have been transferred from organ donors to recipients. Importantly, these tumors had remained dormant in the donors for many years prior to transplant and immediate outgrowth in recipients was the result of immunosuppressants administered to prevent graft rejection. This ability of the immune system to control tumors has also been shown in mice that were injected with a carcinogen. The mice remained tumor-free for over 200 days until they were treated with antibodies that block the activities of T cells, which are important effectors of antitumor immunity. Tumors developed within 10 days of this treatment, confirming that adaptive immunity had prevented tumor growth without destroying the transformed cells. Compilation of the above observations has lead to the theory of immunoediting, which describes the involvement of the immune system in sculpting tumor development. Under this system, if cancer is to develop in an immunocompetent environment, the transformed cells must evolve immune-evasive adaptations that allow them to avoid immune elimination and induction of dormancy. The primary goal of this proposal is to characterize nascent cancer cells and the mechanisms that they employ to circumvent antitumor immunity. The cells will need to be identified and isolated from pre-cancerous patches of mutated cells. To do this, mice will be genetically engineered to inducibly express transforming oncogenes in the epidermis in conjunction with fluorescent marker proteins. This will allow the first direct visualization of immune-controlled, dormant cancer cells. More importantly, comparison of cells isolated from the different stages of immunoediting will reveal the immune-evasive mechanisms that mediate transitions from immune- controlled states to active malignancies. Knowledge of these mechanisms will be used to develop preventative strategies that either target the transformed cells directly or sensitize them to the immune system.
This proposal seeks to identify, characterize, and target non-melanoma skin cancer cells in a pre-clinical stage of their development as a means of cancer prevention. Specific emphasis will be placed on discovering the ways in which cancer cells avoid being destroyed by a person's immune system. The mouse system used for this study, as well as any therapeutic strategies developed, will be applicable to other cancer types, broadening the impact of this prevention discovery strategy.
