Manipulating Immune Regulatory Pathways to Enhance T Cell Stimulation

Abstract

Cancer immunotherapy aspires to treat malignant disease by activating cancer specific immune responses. It is generally accepted that the latter can only be achieved by an approach in which tumor specific T cells are educated to recognize and kill tumor cells, whilst they are furthermore empowered to overcome immunosuppressive mechanisms present both at peripheral sites and in the tumor environment. Dendritic cells (DCs) have been extensively explored as a cellular vaccine for the stimulation of tumor specific T cells. Several strategies have been devised to manipulate these cells to become strongly activated tumor associated antigen (TAA) presenting cells. Our growing knowledge on the biology of DCs and the co- stimulatory as well as inhibitory molecules expressed by them, provides us with opportunities to generate DCs that are capable of hyper-activating cytotoxic T lymphocytes (CTLs) whilst they impact on regulatory T cells (Treg ), which are now well established to be an important contributor to failure of cancer vaccines. In this chapter, we will focus on the cross talk between DCs and T cells mediated by the CD70/CD27 and PD-L1/PD-1 axis as these have been identified as critical pathways in the regulation of immunity versus tolerance.