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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‐1α and IL‐1β, 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‐1β is produced mainly by myeloid cells upon inflammatory stimulation and is active as a mature, secreted molecule. The precursor of IL‐1α (ProIL‐1α) is biologically active; it is constitutively expressed in diverse tissue cells in basal levels, and its expression increases during stress or inflammation. ProIL‐1α is mainly located in the cytosol or it is membrane associated. ProIL‐1α also translocates into the nucleus and binds to chromatin. ProIL‐1α is rarely actively secreted but is released from necrotizing tissues and serves as “alarmin” for initiation of inflammation. In the tumor microenvironment, IL‐1β promotes tumorigenesis, tumor invasiveness, and immunosuppression. On the other hand, membrane‐associated forms of IL‐1α 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.