Immunotherapeutic approaches of IL-1 neutralization in the tumor microenvironment

IL-1 is a pleiotropic cytokine that controls inflammation, immunity, and hemopoiesis. The major IL-1 agonistic molecules are IL-1 alpha and IL-1 beta, which bind to IL-1R type I (IL-1R1) and induce similar biologic functions. The IL-1R antagonist (IL-1Ra) is a physiologic inhibitor of IL-1R1 signaling. In the tumor microenvironment, IL-1 is expressed by malignant, stromal, and infiltrating cells and supports tumor invasiveness and progression. We have shown that in the tumor microenvironment, the IL-1 agonistic molecules act different as a result of their local amounts and their compartmentalization within the producing cells. IL-1 beta is produced mainly by myeloid cells upon inflammatory stimulation and is active as a mature, secreted molecule. The precursor of IL-1 alpha (ProIL-1 alpha) is biologically active; it is constitutively expressed in diverse tissue cells in basal levels, and its expression increases during stress or inflammation. ProIL-1 alpha is mainly located in the cytosol or it is membrane associated. ProIL-1 alpha also translocates into the nucleus and binds to chromatin. ProIL-1 alpha is rarely actively secreted but is released from necrotizing tissues and serves as "alarmin" for initiation of inflammation. In the tumor microenvironment, IL-1 beta promotes tumorigenesis, tumor invasiveness, and immunosuppression. On the other hand, membrane-associated forms of IL-1 alpha support the development of anti-tumor immunity. In cancer patients, both IL-1 agonistic molecules coexist and interact with each other. Here, we discuss the role of IL-1 agonistic molecules in tumor progression and their potential to serve as targets in anti-tumor immunotherapeutic approaches. Our notion on the optimal conditions for IL-1 manipulation is also discussed.