Concise review: engineering the fusion of cytokines for the modulation of immune cellular responses in cancer and autoimmune disorders

Abstract

As our understanding of the basic precepts of immunobiology continue to advance at a rapid pace, translating such discoveries into meaningful therapies for patients has proved challenging. This is especially apparent in the use of cytokine-based immunotherapies for cancer. Unanticipated and serious side effects, as well as low objective response rates seen in clinical trials, have dealt setbacks to the field. Granulocyte-macrophage colony-stimulating factor (GM-CSF) and common γ-chain (γ-c) interleukins are cytokines that have been used as stand-alone immunotherapies with moderate success. Our group has found that the fusion of GM-CSF to members of γ-c interleukins results in the generation of novel proteins with unique signaling properties and unheralded biological effects. These fusion proteins, termed GIFT (GM-CSF interleukin fusion transgenes) fusokines, are the result of combining GM-CSF and a γ-c interleukin into a single, bifunctional polypeptide. In our experience, GIFT fusokines often confer immune cells with a gain of function that cannot be explained by the mere sum of their constituent moieties. They act as bispecific ligands, coupling activated GM-CSF and interleukin receptors together to drive unique downstream signaling events. The synergy that arises from these fusions has shown great promise in its ability to modulate the immune response and overcome maladaptive biological processes that underlie diseases such as cancer and autoimmune conditions. In this review, we discuss the ways in which the GIFT fusokines are able to alter the immune response, particularly in disease states, with a special emphasis on how these novel molecules may be translated into effective therapies in the clinical setting.

Keywords: Cell therapy; Fusion cytokines; Fusion proteins; Immunotherapy; Interleukin biology; Signal transduction.

Figure 1.

GIFT-induced receptor clustering. GIFTs are able to bring together activated GM-CSF and interleukin receptors belonging to the common γ-c family. GM-CSF ligand binding to the GM-CSF receptor triggers the dimerization of α- and β-chains, resulting in the activation of β-chain-associated JAK2/STAT5. γ-c cytokines initiate a similar signaling cascade by bringing together the γ-c and a cytokine-specific IL-Rα. JAK3 associates exclusively with the γ-c in lymphomyeloid cells and activates STAT5 upon IL binding. JAK1 associated with the IL-Rα will activate different STATs (STAT-X), depending on the IL bound. GIFTs trigger the coclustering of all four activated receptor components, resulting in transphosphorylation of IL-Rα-associated STAT-X substrates by JAK2 (dotted arrows). Changes in the balance of STAT phosphorylation events induce a unique GIFT-mediated response that is distinct from canonical GM-CSF- and IL-mediated responses. Abbreviations: γ-c, γ-chain; GM-CSF, granulocyte/macrophage colony-stimulating factor; GMCSFR αc, GM-CSF receptor α-chain; GMCSFR βc, GM-CSF receptor β-chain; IL, interleukin; IL-Rα, IL receptor α-chain.