The Role of Interleukin-1 in the Pathogenesis of Cancer and its Potential as a Therapeutic Target in Clinical Practice

Abstract

Interleukin-1 (IL-1) has long been known to be a key mediator of immunity and inflammation. Its dysregulation has been implicated in recent years in tumorigenesis and tumor progression, and its upregulation is thought to be associated with many tumors. Overexpression of the IL-1 agonists IL-1α and IL-1β has been shown to promote tumor invasiveness and metastasis by inducing the expression of angiogenic genes and growth factors. IL-1 blockers such as anakinra and canakinumab are already approved and widely used for the treatment of some autoimmune and autoinflammatory diseases and are currently being tested in preclinical and human clinical trials for cancer therapy. In this paper we review the most recent discoveries regarding the association between IL-1 dysregulation and cancer and present the novel IL-1 blockers currently being tested in cancer therapy and their corresponding clinical trials.

Keywords: Anakinra; Biologics; Can-04; Canakinumab; Cancer; Inflammation; Interleukin-1; MABp1; Nidanilimab; Xilonix.

Fig. 1

Key mediators of the IL-1 family. A productive IL-1 signaling (green frame) requires the binding of the IL-1 agonists IL-1α or IL-1β to the transmembrane IL-1RI, following the approximation of IL-1RAP and the formation of the signal-transducing heterotrimeric complex. Binding of IL-1Ra to IL-1RI prevents proper formation of the signaling complex and blocks signal transduction. IL-1RII competes with IL-1RI for the binding of the IL-1 agonists but is not able to transduce a signal because of a truncated cytosolic domain. Finally, sIL-1RI is able to bind both agonists and antagonist and therefore plays a double regulatory role, and sIL-1RII is able to bind free agonists and sequester them from proper binding, either on its own or with greater affinities while connected to sIL-1RAP (red frame)

Fig. 2

Novel IL-1 blockers used in clinical trials for cancer therapy. Xilonix, an IL-1α True Human monoclonal antibody, and canakinumab and P2D7KK, IL-1β human monoclonal antibodies, bind to specific regions on their targets, preventing the agonists’ binding to IL-1RI, thus inhibiting downstream signaling. Nidanilimab and CSC012, antibodies specific for IL-1RAP, prevent it from forming the heterotrimeric signaling complex. Lastly, anakinra and IP-1050 are synthetic IL-1Ra agents that compete with the agonists for binding to IL-1RI, thus attenuating the IL-1 signaling system