Role of IL-13 in regulation of anti-tumor immunity and tumor growth

Abstract

Major mediators of anti-tumor immunity are CD4(+) T(h)1 cells and CD8(+) cytotoxic T lymphocytes (CTLs). In tumor-bearing animals, the T(h)1- and CTL-mediated anti-tumor immunity is down-regulated in multiple ways. Better understanding of negative regulatory pathways of tumor immunity is crucial for the development of anti-tumor vaccines and immunotherapies. Since immune deviation toward T(h)2 suppresses T(h)1 development, it has been thought that induction affecting a T(h)2 immune response is one of the mechanisms that down-regulate effective tumor immune responses. Recent studies using T(h)2-deficient signal transducer and activator (Stat6) KO mice demonstrated that this hypothesis was the case. IL-13 is one of the T(h)2 cytokines that has very similar features to IL-4 through sharing some receptor components and Stat6 signal transduction. It has been thought that IL-13 is not as critical for immune deviation as IL-4 since it cannot directly act on T cells. However, recent studies of IL-13 reveal that this cytokine plays a critical role in many aspects of immune regulation. Studies from our lab and others indicate that IL-13 is central to a novel immunoregulatory pathway in which NKT cells suppress tumor immunosurveillance. Here we will describe biological properties and functions of IL-13, its role in the negative regulation of anti-tumor immunity, and effects of IL-13 on tumor cells themselves.

Fig. 1

Receptors for IL-13 and IL-4. IL-4 and IL-13 share the type II IL-4R, which shares the IL-4Rα chain with the type I IL-4R as well. Both receptors use JAK1 and Stat6 for signal transduction, but differ in JAK2 and JAK3. The receptors also have different distributions among cell and tissue types. An additional high affinity receptor for IL-13, IL-13Rα2, has no known function at this time, but has served as a component of a soluble IL-13 inhibitor. See [16, 43] for more detailed treatment

Fig. 2a, b

IL-13 can inhibit anti-tumor immune response and enhance tumor growth. a Inhibitory role of IL-13 in anti-tumor immunity. Tumor antigen (glycolipid) presented by antigen-presenting cells via the CD1d molecule is recognized by and activates CD4⁺ NKT cells. The activated CD4⁺ NKT cell produces IL-13 to suppress CD8⁺ cytotoxic T cells (CTLs) that kill tumor cells. However, since T cells do not express the IL-13 receptors, we postulated intermediate cells that express the IL-13 receptors, that are activated by IL-13 to directly suppress CTL. (Based on Terabe et al. [66, 67] with permission.) b IL-13 is a growth factor for Hodgkin’s lymphoma. Hodgkin’s lymphoma makes IL-13. This IL-13 activates growth of Hodgkin’s lymphoma through the IL-13 receptor–Stat6 pathway in an autocrine fashion [61]. The IL-13 made by Hodgkin’s lymphoma can also suppress anti-tumor immune responses by the mechanism shown in a