New insights into IL-12-mediated tumor suppression

Abstract

During the past two decades, interleukin-12 (IL-12) has emerged as one of the most potent cytokines in mediating antitumor activity in a variety of preclinical models. Through pleiotropic effects on different immune cells that form the tumor microenvironment, IL-12 establishes a link between innate and adaptive immunity that involves different immune effector cells and cytokines depending on the type of tumor or the affected tissue. The robust antitumor response exerted by IL-12, however, has not yet been successfully translated into the clinics. The majority of clinical trials involving treatment with IL-12 failed to show sustained antitumor responses and were associated to toxic side effects. Here we discuss the therapeutic effects of IL-12 from preclinical to clinical studies, and will highlight promising strategies to take advantage of the antitumor activity of IL-12 while limiting adverse effects.

Figure 1

Cellular responses to IL-12 stimulation in the tumor tissue. IL-12 acts mainly on lymphoid cells such as NK cells, T cells and ILCs. All of these subsets increase their IFN-γ secretion upon stimulation and thereby induce most of the tumor-suppressing pathways observed upon IL-12 treatment. Furthermore, IL-12 and IFN-γ potentiate cytotoxic responses by NK cells and CD8 T cells (CD8⁺), involving the production of perforin, granzyme and Fas ligand (Fasl). The secreted IFN-γ is involved in direct tumor vascular responses such as ICAM-1 and VCAM-1 upregulation and inhibition of angiogenesis. The adhesion molecule upregulation is thought to facilitate leukocyte recruitment to the tumor tissue. Moreover, IFN-γ stimulates myeloid cells, which induce the secretion of CXCL9 and CXCL10 and suppress the production of VEGF and MMP-9, yielding in the inhibition of angiogenesis. Moreover, IL-12 stimulates antigen presentation and cross-presentation by APCs and thereby further promotes the cytotoxic activity of CD8 T cells and cytokine response of CD4 T cells. Helper T cell-derived GM-CSF upon IL-12 stimulation has also been shown to mediate the tumor suppressive effect. DC, dendritic cell; MØ, macrophage; NP, neutrophil granulocyte

Figure 2

Different strategies used for IL-12 administration to tumors. The injection of recombinant protein, both systemically and locally, was shown to induce tumor suppression. To more specifically target the tumor tissue, recombinant IL-12 is fused to tumor cell-specific antibodies, so called immunocytokines. Furthermore, various gene therapy approaches such as electroporation and hydrodynamic dynamic injection have been used to deliver an IL-12-encoding plasmid to the tumor site. The IL-12 gene has also been transferred by viral vectors, mainly using engineered adenoviruses. Microspheres and nanoparticles have been utilized for both gene therapy and delivery of the recombinant IL-12 molecule. Moreover, stromal cells, tumor-specific T cells and DCs have been engineered to release IL-12 and transferred into tumors