IL-1RAP, a Key Therapeutic Target in Cancer

Abstract

Cancer is a major cause of death worldwide and especially in high- and upper-middle-income countries. Despite recent progress in cancer therapies, such as chimeric antigen receptor T (CAR-T) cells or antibody-drug conjugate (ADC), new targets expressed by the tumor cells need to be identified in order to selectively drive these innovative therapies to tumors. In this context, IL-1RAP recently showed great potential to become one of these new targets for cancer therapy. IL-1RAP is highly involved in the inflammation process through the interleukins 1, 33, and 36 (IL-1, IL-33, IL-36) signaling pathways. Inflammation is now recognized as a hallmark of carcinogenesis, suggesting that IL-1RAP could play a role in cancer development and progression. Furthermore, IL-1RAP was found overexpressed on tumor cells from several hematological and solid cancers, thus confirming its potential involvement in carcinogenesis. This review will first describe the structure and genetics of IL-1RAP as well as its role in tumor development. Finally, a focus will be made on the therapies based on IL-1RAP targeting, which are now under preclinical or clinical development.

Keywords: IL-1R family; IL-1RAP; cancer; innovative therapies; metastasis.

Figure 4

Cancer types with demonstrated IL-1RAP overexpression [24,25,28,93,95,101,106,110,112]. Created with BioRender.com.

Figure 1

The interleukin 1 superfamily: from the cytokines and their receptors to their main signaling pathway. The ligand (interleukin) binds to its main receptor, which induces the recruitment of the co-receptor (IL-1RAP, IL-18RAP, or SIGIRR). The TIR intra-cellular domains of the receptor/co-receptor complex will recruit MyD88, which activates the MAPK signaling pathway. Finally, MAPKs induce NF-κB or AP-1 transcription factors. The IL-37 is the only interleukin known to activate another pathway, independently of MyD88, which induces the STAT3 transcription factor. Abbreviations: AP-1: activator protein 1; IL: interleukin; IL-1R: interleukin 1 receptor; IL-1Ra: interleukin 1 receptor antagonist; IL-1RAP: interleukin 1 receptor accessory protein; MAPK: mitogen-activated protein kinase; MyD88: myeloid differentiation primary response 88; NF-κB: nuclear factor kappa-light-chain-enhancer of activated B cells; SIGIRR: single Ig IL-1-related receptor; STAT3: signal transducer and activator of transcription 3. Created with BioRender.com.

Figure 2

Structure of IL-1RAP and homogeneity between its different isoforms. (A): Description of the different domains of the mIL-1RAP structure; (B): Predicted 3D structure of IL-1RAP (AlphaFold ID: AF-Q9NPH3-F1); (C): Characteristics of the four isoforms of IL-1RAP; (D): Protein alignment (Clustal Omega) between the four isoforms of IL-1RAP.

Figure 3

Intracellular signaling pathway of IL-1RAP with IL-1R I, IL-33R or IL-36R [20,31,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,87,88,89,90]. The interleukin binds to its main receptor, which induces the recruitment of the co-receptor IL-1RAP. The TIR intra-cellular domains of the receptor/co-receptor complex will recruit MyD88, which activates IRAK4 and IRAK1/2. This complex will then trigger TRAF6, which induces a kinases cascade through MAP3Ks, activating MAPKKs (1) and then stimulating the MAPKs p38, JNK, or ERK1/2. This will finally induce the AP-1 transcription factor. (2) TRAF 6 can also activate IKK, which induces the NF-κB transcription factor. (3) NF-κB can also be stimulated independently from TRAF 6 by IL-1R I and IL-33R (thanks to GAB2) through the activations cascade of PI3K, PDK-1, Akt and IKK. (4) Akt activation will also induce the inhibition of FoxO. (5) IL-33R is also able to stimulate AP-1 independently from TRAF 6 by the activations cascade of GAB2, and Ras/Raf signaling, which activates MEK1/2. Abbreviations: Akt: protein kinase B; AP-1: activator protein 1; ERK: extracellular signal-regulated kinase; FoxO: forkhead box proteins O; Gab2: GRB-associated-binding protein 2; IKK: IkappaB kinase; IL: interleukin; IL-1R I: interleukin 1 receptor type 1; IL-1RAP: interleukin 1 receptor accessory protein; IRAK: interleukin-1 receptor-associated kinase; JNK: c-Jun N-terminal kinase; MAPK: mitogen-activated protein kinase; MAP3K: mitogen-activated protein kinase kinase kinase; MKK: mitogen-activated protein kinase kinase; MyD88: myeloid differentiation response 88; NF-κB: nuclear factor kappa-light-chain-enhancer of activated B cells; NIK: NF-κB-inducing kinase; p38: MAPK p38; PDPK1: phosphoinositide-dependent Kinase-1; PI3K: phosphoinositide 3-kinase; Raf: “rapidly accelerated fibrosarcoma;” Ras GTP: “rat sarcoma virus” guanosine triphosphatase; SHP2: Src homology region 2 domain-containing phosphatase-2; TAB: TGF-beta activated kinase 1 (MAP3K7) binding protein; TAK1: mitogen-activated protein kinase kinase kinase 7 (MAP3K7); TRAF: TNF receptor-associated factors. Created with BioRender.com.

Figure 5

Involvement of IL-1RAP in tumor development. Created with BioRender.com.

Figure 6

Involvement of the IL-1 family axis in the TME. Created with BioRender.com.