Lung cancer is the leading cause of cancer deaths worldwide. The reasons for the high death rate stem from the usually late diagnosis of the disease and lack efficient treatments for advanced lung cancer. There is some evidence that memory T cells can play a role in the pathogenesis of lung cancer, but, as is the case for other types of cancer, lung cancer appears to be associated with T cell dysfunction that may impede effective anti-tumor responses. In general, however, the role of T cells in the pathogenesis of lung cancer, and their potential role in immunotherapy, remains poorly understood. One reason for our incomplete knowledge of the role of memory T cells in lung cancer is the lack of an experimental model that allows non-invasive tumor imaging and clear, well-defined, tumor-associated T cell determinants that can be used to carefully dissect the tumor-specific T cell response. The overall hypothesis of this application is that memory T cell responses will influence the pathogenesis of lung adenocarcinoma, but that tumor-specific T cell responses will become progressively less functional as tumor burden increases. To this end, the goal of the current application is to develop a novel mouse model of lung adenocarcinoma that will allow detailed tumor monitoring and in depth T cell analysis. We will build upon an existing activated K-ras model of lung adenocarcinoma and modify the model to include two well-defined T cell epitopes (a CD4 and a CD8 epitope) from lymphocytic choriomeningitis virus (LCMV), GP33 and GP61, fused directly to the N-terminus of the oncogenic activated K-ras protein. Thus, this new GP33/61-K-rasG12D mouse model of lung adenocarcinoma will allow detailed evaluation of tumor progression as well as state of the art analysis of the dynamics and quality of the tumor- specific T cell response. A major strength of this application is that it brings together the expertise of both our labs in the areas of animal models of lung cancer (Kissil lab) and memory T cell differentiation and T cell dysfunction (Wherry lab). By simultaneous monitoring of tumor development as well as the tumor-specific T cell response, this model should allow considerable advances in our understanding of the role of T cell responses in the pathogenesis of lung adenocarinoma in an in vivo physiological scenario that closes recapitulates the human disease.
Lung cancer is the leading cause of cancer deaths worldwide, in spite of considerable efforts and major advancements to our understanding of this disease. Clearly, effective treatments are badly needed. The immune system, and especially T cells, has considerable anti-cancer potential and thus represent a potential powerful tool in the fight against lung cancer. The studies in this proposal will shed light on the role of the immune system and, in particular, on the relationship between developing lung tumors and antitumor T cell responses. This understanding is central to devising effective immunological strategies to treat lung cancer.
