GM-CSF-based fusion cytokines as ligands for immune modulation

Chromosomal translocations that combine distinct functional domains of unrelated proteins are an experiment in nature. They demonstrate how endogenous regulatory checkpoints can be overridden by altered cell biochemistry, informing a means to engineering an aberrant signal that the cell is incapable of counterregulating. Thus, our laboratory and others have synthesized fusions of GM-CSF with peptides, ILs, and chemokines, which we have termed fusokines, with the aim of inducing an enhanced immune response against cancer, aiming to overcome the maladapted biological processes causing disease. In doing so, we found that these fusokines did not behave as merely the sum of their natural unfused counterparts, but as entirely novel ligands co-opting their cognate receptor to communicate a unique message to responsive cellular targets. In this review, we discuss how fusion proteins combining different bioactive ligands can alter immune responses and briefly discuss the regulatory pathways that they circumvent.