Immunotherapy of cancer by IL-12-based cytokine combinations

Abstract

Cancer is a multi-faceted disease comprising complex interactions between neoplastic and normal cells. Over the past decade, there has been considerable progress in defining the molecular, cellular and environmental contributions to the pathophysiology of tumor development. Despite these advances, the conventional treatment of patients still generally involves surgery, radiotherapy and/or chemotherapy, and the clinical outcome for many of these efforts remains unsatisfactory. Recent studies have highlighted the feasibility of using immunotherapeutic approaches that seek to enhance host immune responses to developing tumors. These strategies include immunomodulatory cytokines, with TNF-alpha, type I or type II IFNs, IL-2, IL-12, IL-15 and IL-18 being among the most potent inducers of anti-tumor activity in a variety of preclinical studies. More recently, some exciting new cytokines have been characterized, such as IL-21, IL-23, IL-27 and their immunomodulatory and antitumor effects in vitro and in vivo suggest that they may have considerable promise for future immunotherapy protocols. The promise of cytokine therapy does indeed derive from the identification of these novel cytokines but even more fundamentally, the field is greatly benefiting from the ever-expanding amount of preclinical data that convincingly demonstrate synergistic and/or novel biologic effects, which may be achieved through the use of several combinations of cytokines with complementary immune-stimulating capabilities. One cytokine in particular, IL-12, holds considerable promise by virtue of the fact that it plays a central role in regulating both innate and adaptive immune responses, can by itself induce potent anticancer effects, and synergizes with several other cytokines for increased immunoregulatory and antitumor activities. This review discusses the antitumor activity of IL-12, with a special emphasis on its ability to synergize with other cytokines for enhancement of immune effector cell populations and regulation of host-tumor cell interactions and the overall tumor microenvironment.

Figure 1

Schematic depiction of the IL-2 and IL-12 cytokine/receptor families and their functions. IL-2, IL-7 and IL-15 are cytokines that interact with receptor complexes that contain a common gamma (γ_c) chain. Binding of the appropriate cytokines to the γ_c containing receptor primes T and NK cells for their activation and proliferation (reviewed in [17]). IL-12, IL-23 and IL-27 are heterodimeric cytokines that bind receptors with similar structure. The IL-12 family of cytokines activates T and NK cells for enhanced effector functions.

Figure 2

Schematic depiction of the IL-18 and IL-12 cytokine/receptor families and their functions. IL-18 and IL-1 interact with receptor complexes comprising homologous alpha and beta subunits and signal through the MyD88 and IRAK adapter molecules. IL-1 and IL-18 are potent activators of NFκB signaling which results in leukocyte activation, IFN-γ production and inflammation. IL-12, IL-23 and IL-27 are heterodimeric cytokines that bind receptors with similar structure. The IL-12 family of cytokines activates T and NK cells for enhanced effector functions.