IL-23 and the Tumor Microenvironment

The tumor microenvironment (TME), which assists in the development, progression, and metastasis of malignant cells, is instrumental in virtually every step of tumor development. While a healthy TME can protect against malignancy, in an unhealthy state, it can result in aberrant cellular behavior and augment tumor progression. Cytokines are one component of the TME, therefore, understanding the composition of the cytokine milieu in the tumor microenvironment is critical to understand the biology of malignant transformation. One cytokine, interleukin (IL)-23, has received particular scrutiny in cancer research because of its ability to manipulate host immune responses, its role in modulating the cells in TME, and its capacity to directly affect a variety of premalignant and malignant tumors. IL-23 belongs to the IL-12 cytokine family, which is produced by activated dendritic cells (DC) and macrophages. IL-23 acts by binding to its receptor consisting of two distinct subunits, IL-12Rβ1 and IL-23R. This, in turn, leads to janus kinase (JAK) activation and signal transducer and activator of transcription (STAT) 3/4 phosphorylation. There have been contradictory reports of pro- and antitumor effects of IL-23, which likely depend on the genetic background, the type of tumor, the causative agent, and the critical balance of STAT3 signaling in both the tumor itself and the TME. Clinical trials of IL-12/23 inhibitors that are used to treat patients with psoriasis, have been scrutinized for reports of malignancy, the most common being nonmelanoma skin cancers (NMSCs). Continued investigation into the relationship of IL-23 and its downstream pathways holds promise in identifying novel targets for the management of cancer and other diseases.