Lung cancer remains the major cancer-related cause of death in the Western World and intense efforts are directed toward the development of immunotherapy for the treatment of this disease. While immunotherapy targeting cytotoxic T (CD8+ T) lymphocytes has been successful in several malignancies, such as melanoma and prostate cancer, it has demonstrated only limited success in lung cancer. Based on our laboratory’s work in lung transplantation, where we have demonstrated a tolerogenic role for alloreactive CD8+ T cells, we have now generated preclinical animal data which demonstrates that, unlike the case for other malignancies, the presence of conventional CD8+ T cells can accelerate the growth of both transplantable as well as carcinogen-induced lung cancer in a murine model. In this Merit Award application we propose a series of coordinated but non-overlapping specific aims to delineate the tolerogenic role of CD8+ T cells in lung cancer, identify mechanisms responsible for CD8+ T cell-mediated downregulation of the immune response, as well as define the interaction of CD8+ T cells with natural killer cells. This proposal will extend our understanding of lung cancer-specific immunoregulation and generate novel preclinical data that can be utilized for rational design of lung cancer- specific novel therapeutic approaches for Veterans and the general population.