Tumor Immunology

In the past few years, we begun to use mouse models to study tumor immunology. A long-standing goal of cancer immunotherapy is to use tumor-infiltrating T cells to fight cancer, yet many critical questions remain about the nature of these cells and how to best exploit them. The failure of infiltrating T cells to eliminate tumors has been attributed to tumor evasion via local immune suppression or tolerance induction; however, studies of immune-tumor interactions have predominantly utilized transplant models of cancer, which may have little relevance to the human disease. Thus, we have undertaken studies of tumor immune surveillance based on the autochthonous model of lung adenocarcinoma established in the Jacks lab (in which oncogenic K-ras is activated by Cre recombinase with temporal and spatial control to initiate tumor formation). A major strength of autochthonous mouse models of cancer is that tumors develop in animals with normal immune function. Therefore, tumor progression may be shaped by an interaction with the immune system. In order to study the response of T lymphocytes to tumor-specific antigens as well as the mechanisms of tumor evasion of the immune response, we have recently developed next-generation NSCLC models in which well-studied antigens are expressed specifically in developing tumor cells. Two strategies have been initiated toward this goal. One utilizes stably-integrating lentiviral vectors that express simultaneously both the antigens and Cre recombinase, while the other involves generation of a conditional knock-in allele of the antigens that can be activated concurrently with oncogenic K-ras following expression of Cre. In both systems, the antigenic peptides have been fused to a Firefly Luciferase gene, enabling us to monitor tumor size over time using in vivo bioluminescence-imaging technology. With these novel tools, we are studying the anti-tumor efficacy of tumor-reactive T cells and the mechanisms by which these cells are suppressed or tolerized during the course of tumor progression. We expect that an improved understanding of the regulatory processes that allow tumors to develop in the context of a functional immune system will be critical if immune-based therapies are eventually going to be effective in the treatment of cancer.