T cell activation is initiated by signaling through the TCR after binding to MHC-presented antigen. Both positive and negative co-regulatory signaling can modify this original activating signal. T cell co-regulation is provided by receptors on the T cell surface membrane. Inhibitory signals are provided by CTLA4 or PD-1, while co-stimulation is provided by CD28, 4-1BB, OX40, or GITR. These signals are being studied in the laboratory and at the clinical level in order to therapeutically modulate T cell responses to tumor cells. T cells can recognize tumor antigens in the same way that these immune cells recognize bacteria, viral antigens, and other foreign peptides. If appropriately activated by the tumor antigen, the immune system can mediate an antitumor gene response. Unfortunately, immune cells with antitumor specifi city are not present in abundance and are often inhibited by tumor expression of CTLA4 or PD-1 ligands. Thus manipulation of co-regulatory signals can be used as a strategy by which to strengthen the immune response, via augmentation of T cell co-stimulation and/or blockade of inhibitory signals, in order to effectively treat cancer. In this chapter we review the basic principles and science as well as the ongoing clinical efforts in this area that have had recent success and offer additional promise.
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