Searching for new mechanisms of NK cells defense against the suppressive influence of selected elements of the tumor environment

According to the World Health Organization (WHO), malignant tumors are the leading cause of death worldwide, causing approximately 8.2 million deaths annually. Each year, approximately 14 million new cases of malignant neoplasm are diagnosed. According to the latest reports from the International Agency for Research on Cancer (IARC), the annual number of cancer cases is expected to increase from 14 million in 2012 to 22 million over the next two decades. In Poland, malignant neoplasms are the second most common cause of death, after cardiovascular diseases. While mortality from cardiovascular disease has decreased significantly in recent years, cancer mortality has significantly increased. Indeed, mortality due to cancer in 2008 was higher in Poland than in 1980, constituting 25.8% of all deaths, while mortality due to cardiovascular diseases in 2008 was lower by about 39% compared to 1980. An important fact is that both the incidence and mortality due to cancer in Poland are at one of the highest levels among all EU countries. According to the latest report from the National Cancer Registry, in 2012 there were over 152,000 newly diagnosed people with malignant neoplasms and over 94,000 deaths related to these diseases. Classic forms of therapy, such as surgery, chemotherapy and radiotherapy, are currently only partially effective in the fight against cancer. Despite numerous advances in genetics and molecular biology, virology, chemistry, and pharmacology, cancers continue to successfully avoid treatment. However, thanks to increasing innovation, scientific discoveries and technological progress, the understanding of cancer is undergoing a profound transformation. While still in its infancy, so-called personalized medicine is emerging as a new paradigm in cancer treatment. Part of this new paradigm is the understanding of cancer as a systemic disease in which there is an intense dialogue between the cancer and the host, especially the host's immune system. It should be noted that in the light of the current state of knowledge, the ability of the human immune system to specifically recognize cancer-related molecules makes it an extremely precise tool and highly suitable for personalizing cancer treatments. This is particularly true for cancers associated with infection by viruses such as HCV, HBV or HPV, which, according to the WHO, are responsible for almost 20% of cancer deaths in low- and middle-income countries. Science Magazine called cancer immunotherapy "Breakthrough of 2013". Indeed, immuno-oncology is one of the most vigorously developing areas of cancer research today, and raises great hopes for a cure for these debilitating diseases. It is anticipated that in the next decade, immunotherapies will be the mainstay of treatment in 60% of cancer types. Before the immune system can be used to its fullest effectiveness in the fight against cancer; however, several challenges need to be dealt with. These challenges can be divided into two main areas: 1. understanding the mechanisms of cancer escape from the immune system; 2. identification of the most effective anti-cancer tools derived from the immune system. There is ample evidence that cancer employs at least several different mechanisms to avoid being controlled by the immune system. One of these mechanisms is based on the increase in oxidative stress conditions and high levels of reactive oxygen species (ROS) such as hydrogen peroxide within the tumor mass. Another important element is the conditions of reduced oxygen availability in the neoplastic environment, called hypoxia.Under such conditions, numerous anti-cancer mechanisms in the cells of the immune system are switched off. Therefore, it becomes important to understand how the cells of the immune system can adapt to such a hostile environment. This is one of the objectives of this proposal. Natural killer (NK) cells are part of the human immune system and act on the borderline between innate and acquired immunity. Numerous publications suggest that the proper functioning of NK cells plays an important role in the fight against viral infections and cancer. Therefore, intensive research is currently being carried out to successfully use these cells as a therapeutic tool in the fight against cancer. Unfortunately, the anti-tumor activity of NK cells can be suppressed by high levels of oxidative stress or the tumor's hypoxic environment, which in turn can seriously hinder their use in oncology. For this reason, in our project we try to understand in detail the mechanisms that take place in NK cells under conditions of oxidative stress and hypoxia. On this basis, we want to select mechanisms that can potentially protect NK cells against the inhibitory effects of oxidative stress and hypoxia. In the final stage of the project, we intend to create NK cells that will be able to overcome the inhibitory effect of the tumor environment and effectively kill the tumor cells. In this project, we will use a modern RNA sequencing technique to capture changes in NK cells subjected to oxidative stress and hypoxia. The conducted research will provide us with a wide range of information on changes in gene expression in NK cells under the conditions associated with neoplasms. From the range of information available, we will select those that will be of importance in the fight against cancer cells by NK cells. Based on the acquired knowledge, we will modify NK cells so that they can effectively recognize and kill cancer cells under the hostile conditions of oxidative stress and hypoxia. By deciding on such an ambitious project, we want to contribute to the identification and understanding of the molecular mechanisms regulating the activity of NK cells in the tumor environment, and then use the acquired knowledge to create NK cells, resistant to the inhibitory action of tumors. The knowledge we gain may in the future lead to the improvement of therapeutic methods that use modified NK cells as a therapy against cancer. This therapy can also be used in other human diseases.