Targeting IL4/IL4R for the treatment of epithelial cancer metastasis

Abstract

While progress has been made in treating primary epithelial tumors, metastatic tumors remain largely incurable and still account for 85-90 % of all cancer-related deaths. Interleukin-4 (IL4), a Th2 cytokine, and the IL4/IL4 receptor (IL4R) interaction have well defined roles in the immune system. Yet, IL4 receptors are over-expressed by many epithelial cancers and could be a promising target for metastatic tumor therapy. The IL4/IL4R signaling axis is a strong promoter of pro-metastatic phenotypes in epithelial cancer cells including enhanced migration, invasion, survival, and proliferation. The promotion of breast cancer growth specifically is also supported in part by IL4-induced glutamine metabolism, and we have shown that IL4 is also capable of inducing glucose metabolism in breast cancer cells. Importantly, there are several types of FDA approved medications for use in asthma patients that inhibit the IL4/IL4R signaling axis. However, these approved medications inhibit both the type I IL4 receptor found on immune cells, and the type II IL4 receptor that is predominantly expressed by some non-hematopoietic cells including epithelial cancer cells. This article reviews existing therapies targeting IL4, IL4R, or IL4/IL4R signaling, and recent findings guiding the creation of novel therapies that specifically inhibit the type II IL4R, while taking into consideration effects on immune cells within the tumor microenvironment. Some of these therapies are currently in clinical trials for cancer patients, and may be exploitable for the treatment of metastatic disease.

Keywords: Cytokine; IL4; IL4 receptor; Metastasis; Proliferation; Survival.

Figure 1. IL4/IL4 receptor signaling in epithelial cancer cells and hematopoietic cells of the tumor microenvironment (TME)

IL4 induces heterodimerization of the IL4Rα and γC subunits to form the type I IL4 receptor in hematopoietic cells including lymphocytes (depicted). This results in the activation of JAK proteins. The two main pathways activated after the phosphorylation of JAKs in response to IL4 in immune cells are the IRS/PI3K/AKT pathway and the JAK/STAT6 pathway. Activation of these pathways in lymphocytes results in the transcription of IL4 responsive genes and the promotion of pro-growth phenotypes. IL4 has also been shown to activate mTOR in T lymphocytes for the regulation of differentiation. Some non-hematopoietic cells including epithelial cancer cells can express the type II IL4R, consisting of the IL4Rα and IL13Rα1 subunits. IL4 directly promotes pro-growth and pro-metastatic phenotypes downstream of the type II IL4R in epithelial cancer cells through several signaling pathways including PI3K/AKT, MAPK/ERK, JAK/STAT6, and mTOR.

Figure 2. IL4 binds and activates the type I IL4 receptor on hematopoeitic cells, and the type II IL4R on myeloid cells of the tumor microenvironment (TME) to promote metastatic tumor growth

Th2 T lymphocytes, including CD4(+) lymphocytes, are one of the main producers of IL4 in the tumor microenvironment (TME) that have been shown to promote metastasis. In the TME, IL4 promotes tumor growth and metastasis by polarizing macrophages to M2 tumor associated macrophages (TAMs), impairing the cytolytic ability of CD8(+) T lymphocytes by polarizing them to type 2 cytotoxic T cells (Tc2), and activating myeloid-derived suppressor cells (MDSCs). These activated MDSCs no longer differentiate into mature macrophages, dendritic cells, or granulocytes, and instead adopt a pathological tumor-promoting phenotype. These pro-tumor MDSCs suppress the anti-tumor immune functions of T cells and promote tumor growth and metastasis in epithelial cancer cells. MDSCs can also produce IL4, which can act in an autocrine fashion, and TAMs can stimulate the production of IL4 from CD(4)+ lymphocytes.