Regulation of Carcinogenesis by IL-5 and CCL11: A Potential Role for Eosinophils in Tumor Immune Surveillance

Abstract

The role of the immune system in the surveillance of transformed cells has seen a resurgence of interest in the last 10 years, with a substantial body of data in mice and humans supporting a role for the immune system in host protection from tumor development and in shaping tumor immunogenicity. A number of earlier studies have demonstrated that eosinophils, when recruited into tumors, can very effectively eradicate transplantable tumors. In this study, we investigated whether eosinophils also play a role in tumor immune surveillance by determining the incidence of methylcholanthrene (MCA)-induced fibrosarcomas in IL-5 transgenic mice that have greatly enhanced levels of circulating eosinophils, CCL11 (eotaxin-1)-deficient mice that lack a key chemokine that recruits eosinophils into tissues, and the eosinophil-deficient mouse strains, IL-5/CCL11−/− and ΔdblGATA. It was found that MCA-induced tumor incidence and growth were significantly attenuated in IL-5 transgenic mice of both the BALB/c and C57BL/6 backgrounds. Histological examination revealed that the protective effect of IL-5 was associated with massively enhanced numbers of eosinophils within and surrounding tumors. Conversely, there was a higher tumor incidence in CCL11−/− BALB/c mice, which was associated with a reduced eosinophil influx into tumors. This correlation was confirmed in the eosinophil-deficient IL-5/CCL11−/− and ΔdblGATA mouse strains, where tumor incidence was greatly increased in the total absence of eosinophils. In addition, subsequent in vitro studies found that eosinophils could directly kill MCA-induced fibrosarcoma cells. Collectively, our data support a potential role for the eosinophil as an effector cell in tumor immune surveillance.

Identification of Innate IL-5–Producing Cells and Their Role in Lung Eosinophil Regulation and Antitumor Immunity

“…Together with our finding that innate IL-5-producing cells were most abundant in the lung, it seems likely that lung eosinophil largely depends on IL-5. IL-5 may also participate in prolonged activation of eosinophils in the context of a persistent tumor burden, as indicated previously (30), and in fact, rIL-5 treatment prolonged eosinophil migration toward tumor cells in this study. Natural IL-5 production thus recruits sufficient eosinophils to the lung and generates a microenvironment that prevents establishment of tumor cells and potentially of invasion by foreign pathogens.…”

“…One of the functions of eosinophils primed by Th2 cytokines is tumor surveillance and clearance (25,30). Given that deficiency of IL-5 causes impaired eosinophil recruitment to the lung (Fig.…”

“…7A, 7B). As IL-5 overexpression resulted in increased tumor-infiltrating eosinophils (30), the location of eosinophils in relation to tumor metastases was analyzed by H&E staining (Supplemental Fig. 3E) and immunohistochemistry (Fig.…”

“…Interestingly, exogenous treatment of tumor-bearing mice with IL-5 led to prolonged survival of the mice (29). In this case, IL-5-dependent augmentation of eosinophil infiltration into tumor sites was necessary for tumor surveillance (30).…”

Human Eosinophils Exert TNF-α and Granzyme A-Mediated Tumoricidal Activity toward Colon Carcinoma Cells

“…Even though the beneficial effect of TATE remains controversial, the presence of eosinophils appears as an indicator of good prognosis indicator in some cancers, such as head and neck cancers (7)(8)(9) and gastrointestinal cancers (10), particularly in colorectal cancers, in which high eosinophil counts were associated to increased 5-y survival (11). Clinical observations that eosinophil accumulation in intestinal tumors was associated to a better prognosis have been recently supported by experimental data in murine models (12)(13)(14).…”