Abstract A18: Mouse models of autochthonous cancer to study local immune subversion.

Abstract

Abstract The tumor environment delivers suppressive signals to the immune system, which impair the effector function of tumor-infiltrating lymphocytes. The identity of these signals, their targets and their mode of action, however, are largely unresolved. We use TRAMP mice, a well-known autochthonous murine model for prostate cancer, to study the interaction of the adaptive immune system and cancer cells in order to investigate which cell types and molecules are crucial in deviating immune surveillance. Tumorigenesis in TRAMP mice is driven by SV40 large T (SV40LT), which allows monitoring of specific CD8 T cell responses to the tumor. We analyzed quantitative and qualitative aspects of the tumor-specific T cell response in the spleen, the draining and non-draining lymph nodes and in the tumor of TRAMP mice. Interestingly, this mouse model shows CD8 T cell tolerance towards epitope IV but not epitope I of SV40LT when infected with recombinant vaccinia viruses expressing these epitopes. However, when transferring TCR transgenic CD8 T cells specific for epitope I, we observed rapid local and peripheral immune subversion of adoptively transferred cells in tumor-bearing animals. Homing and proliferation were not affected, but effector functions of these cells were greatly impaired. Furthermore, this immunosuppression was more severe locally at the tumor site than in the periphery. When using a combination of blocking antibodies for co-inhibitory molecules (PD-1, CTLA-4 and TIM-3), we could restore to some extent the function of transferred cells in the periphery, but not at the tumor site. In parallel, we are in the process of generating an inducible CreERT/LoxP-based model to express the immunologically well-characterized oncogene SV40LT with the luciferase in a tissue specific fashion. This model will allow sensitive detection of arising tumors and precise dissection of tumor-specific immunity over time. By comparing fundamentally different target tissues, we may find mechanisms that are active in every malignancy and some that are organ-specific. Citation Format: Ali Bransi, Hideo Yagita, Alexander Knuth, Maries van den Broek. Mouse models of autochthonous cancer to study local immune subversion. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology: Multidisciplinary Science Driving Basic and Clinical Advances; Dec 2-5, 2012; Miami, FL. Philadelphia (PA): AACR; Cancer Res 2013;73(1 Suppl):Abstract nr A18.