Eosinophils and colon cancer

Colon cancer is one of the leading causes of deaths worldwide. New therapies against colon cancer, however, such as the immunotherapy, that enables the bodys own immune system to reject the cancer, are slowly emerging. The tumor mass not only consists of cancer cells but also of white blood cells that infiltrate the tumor during the development in order to combat tumor growth through an immunosurveillance program. In our project, we focus on a special type of white blood cells, the eosinophils, and on the actions they have in the development of the cancer, whether they promote or reject tumor growth. From clinical studies we know that the number of eosinophils counted in tumors correlate with longer patient survival after resection of the tumor. In our project, we, therefore, propose that eosinophils that are present in tumors of the colon are able to reduce the growth of tumors. To investigate this theory, we will make use of transgenic mice that either lack or enhance production of eosinophils, and in which an experimental form of colon carcinoma is induced. With this approach, we will be able to find out whether presence of eosinophils within the tumor influences tumor growth and whether eosinophils are able to orchestrate the actions of other white blood cells, like T-cells that are known to exert beneficial effects in immunotherapy. Samples from human colon carcinoma will be also checked for the presence of eosinophils and markers of disease severity, in order to correlate tumor burden with the number of eosinophils. In cell culture studies of human eosinophils and colon carcinoma cells, we will investigate what kind of interaction exists between tumor cells and white blood cells, which will help us to understand how eosinophils contribute to tumor rejection and whether eosinophils would be useful in immunotherapy. The current proposal elucidates the unknown role of eosinophils in colon cancer. In light of the fact that new immunotherapies are now beginning to be implemented for various types of cancer, we want to add to the understanding of the role of eosinophils in tumor biology, and we want to create a basis for the implementation of effective immunologic treatment options against colon cancer.

Interleukin 33 enhances the fight of eosinophils against colon cancer Eosinophils are white blood cells that are increased during allergies and diseases caused by parasites (e.g. infestation of the intestine with worms). They belong to the innate immune system, a cell population that acts as a first responder against microbial infections. However, it has also been known for many years that in several types of cancer, such as colon cancer, eosinophils can infiltrate tumors to quite a large extent. Thus, the amount of infiltrated eosinophils correlates with tumor growth. An increased presence of eosinophils in tumors of colon cancer is also associated with a better prognosis. So far, it is unclear how eosinophils slow tumor growth in colon cancer. Eosinophils are cells with many functions and one of their most important is degranulation, i.e. the release of cell-toxic proteins that enables them to attack not only parasites, but also tumor cells. In order to increase this cell-toxic effect, eosinophils have to be activated by so-called cytokines, small proteins that act as cell regulators. One of these cytokines is interleukin 33, which can be detected in many tumors. In our project, we investigated the effect of interleukin 33 in preclinical models of colon cancer with the help of mice that do not produce eosinophils. We were able to show that therapy with interleukin 33 led to a decrease in tumor growth. We observed that application of interleukin 33 promoted the infiltration of eosinophils into the tumors. Simultaneously, the activity status of eosinophils was also increased, an important prerequisite for their tumoricidal activity. Interleukin 33 therapy led to an increased degranulation of eosinophils. Their survival and ability to attack tumor cells were also greatly increased. Interleukin 33 appears to act directly on eosinophils. It can increase the number of factors that attract eosinophils to the tumor site. In contrast, the tumor-reducing effect of interleukin 33 was abolished in eosinophil-deficient mice. When the eosinophil-deficient mice received activated eosinophils, the tumor-reducing effect of interleukin 33 was restored. This supported our hypothesis that the presence of eosinophils is indispensable for the tumor-reducing effect of interleukin 33. The possibility of multiplying the body's own immune cells, activating them and transferring them to the patient is already being investigated as part of an immunotherapy against tumors. Based on the results of our project, interleukin 33 and eosinophils could become part of the immunotherapeutic repertoire against colon cancer.