Enhanced Anti-Tumor Immunity by Breaking Immune Tolerance.

Abstract

The immune system plays a major role in the surveillance against tumors. However, tumor cells adapt different strategies to avoid attack from the immune system. Different approaches of immunotherapy have been developed based on the understanding of these strategies. Inducing immune tolerance is one of the major strategies used by tumor cells to escape from immune surveillance. Immune tolerance can be divided into central tolerance and peripheral tolerance. Central tolerance is imposed during the development of T cells in the thymus, while peripheral tolerance occurs after T cells are exported into the periphery. Since most tumor antigens are self-antigens expressed in the thymus, clonal deletion will induce tolerance to these tumor antigens. Regulatory T cells (Tregs) are important to maintain the peripheral tolerance. The increased number of Tregs found in cancer patients and the existence of tumor specific-Tregs indicates that Tregs may suppress the anti-tumor immunity in the periphery. With the understanding of signal pathways involved in immune tolerance, it is possible to break immune tolerance to tumor cells by targeting molecules involved in these pathways and thus, enhance anti-tumor immunity. In chapter II, using the endogenous prostate cancer model TRAMP, we targeted the LTalpha gene to break central tolerance. Our data demonstrated that both the targeted mutation of the LTalpha gene and soluble receptor blocking of the LTalpha protein rescued T cells with high avidity to tumor antigen in the thymus. These treatments also substantially reduced the risk of prostate cancer, with almost complete ablation of metastasis. In chapter III, we targeted the co-stimulatory molecules B7-1 and B7-2 to break both central tolerance and peripheral tolerance. Both the rescue of tumor antigen-specific T cells and a reduction of Tregs were achieved by anti-B7-1 and anti-B7-2 mAbs. Correspondingly, delayed tumor development was observed in TRAMP model and in a transplanted MC38 tumor model treated with anti-B7 antibodies. In chapter IV, to further understand the development of Tregs in the thymus, we studied the roles of thymic APCs in Treg development. We found both the thymic stroma-derived APCs and bone marrow-derived APCs are required for Treg development in the thymus.