Natural Immune surveillance versus induced anti-tumor immunity: insights for immunotherapy

Pamela S. Ohashi, Kiichi Murakami, Alisha R. Elford and Matthew A. Gronski

We have established a model to examine the consequences of tumor growth on T cell tolerance versus immune surveillance. We have shown that tumor growth breaks both immunological ignorance and tolerance. In our model, RIP-Tag2 transgenic mice express the SV40 large T antigen under the control of the rat insulin promoter (RIP). This predisposes animals to the spontaneous development of b-islet cell tumors (insulinomas). Since T cells are known to be tolerant to the SV40 large T antigen, we have introduced another transgene, the lymphocytic choriomeningitis virus glycoprotein (LCMV-gp), that is expressed by the b-islet cells (RIP-gp). Tumor specific T cells are monitored using the P14 TCR transgenic model, which expresses a transgenic TCR specific for LCMV-gp and H-2D^b. Detailed analysis of this model has suggested that the tumor specific T cells are not tolerized, but participate in a weak natural immune surveillance. Our recent studies have compared the natural spontaneous immune response to tumors with activation of an anti-tumor response using various strategies. Our model has shown that natural immune surveillance is limited in several ways. In addition, our recent studies have examined the consequences of activation of an anti-tumor response with lower affinity TCR ligands. Importantly, anti-tumor immunity and autoimmunity are limited by both the affinity between the TCR and activating ligand as well as negative regulatory mechanisms.