Natural killer cells of the immune system can fend off malignant lymphoma cells and thus are considered a promising therapeutic approach. However, in the direct vicinity of the tumor they lose their effect. Scientists of Helmholtz Zentrum München have now elucidated which mechanisms block the natural killer cells and how this blockade could be lifted. The results were recently published in the European Journal of Immunology.
Natural killer cells (NK cells) are part of the immune system and provide an innate immunity against exogenous and altered endogenous structures. This also appears to apply to tumor cells, against which the body could develop immunity as it does against pathogens, e.g. against viruses. Tumors of the lymph nodes, called lymphomas, are malignant neoplasms that originate from the B cells or T cells of the lymphatic system. B cell lymphomas are very difficult to treat - which is why innovative approaches to therapy are needed. Earlier studies have shown that NK cells have the potential to attack B lymphoma cells and are therefore considered a possible approach to new treatment strategies. In the living organism, however, tumor control by NK cells has been found to be clearly limited.
NK cells become functionally impaired in the tumor microenvironment
In their experiments, the team led by Prof. Dr. Ralph Mocikat of the Institute of Molecular Immunology (IMI) at Helmholtz Zentrum München, found that the NK cells in the immediate vicinity of the tumor showed reduced function. If the cells were placed in a normal environment, their function could be restored within a few hours. This suggests that the factors responsible for the inactivation of the NK cells derive from the tumor itself.
An inflammatory cytokine inactivates NK cells - altered surface molecules block immune activation
The scientists engaged in the research project identified two important tumor-specific factors that are associated with impaired NK cell function. First, a specific inflammatory cytokine (IL-10) is indirectly involved in the inactivation of NK cells. Second, the tumor cells develop protective mechanisms against the NK cells. Thus, the research group showed that specific surface molecules of the tumor cells (NKG2D ligands) which NK cells could bind are down-regulated. Consequently, the NK cells lack an important activation mechanism and are no longer able to carry out cytotoxic activity. Despite the inhibitory strategies of the tumor cells, at an early stage the NK cells produce the cytokine interferon-gamma (IFN-γ), the scientists reported. IFN-γ is essential to activate further immune responses that support the fight against the tumor.
Immunotherapy possible using NK cells - with optimization potential
"Our results show that the transfer of NK cells is a possible strategic option to treat B cell lymphoma. According to our findings, this therapeutic approach can be optimized when transferred NK cells are already activated in vitro prior to their injection, thus bypassing the missing activation potential in the tumor microenvironment. An additional injection of IFN-γ or of antibodies against IL-10 could further support the immune activity," said study leader Mocikat.
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Further Information
Background: The Wilhelm Sander Foundation supported this project with € 85,000 and gave it a very positive assessment after its completion. The purpose of the foundation is to promote medical research, in particular the fight against cancer. With more than 2000 funded projects and approximately € 220 million in funds distributed since its inception, the Wilhelm Sander Foundation takes a prominent place in medical research funding in Germany. The foundation's endowment comes from the estate of the entrepreneur Wilhelm Sander; in 2015 the foundation is celebrating its 40th anniversary.
Original Publication: Belting et al. (2015), Critical role of the NKG2D receptor for NK cell-mediated control and immune escape of B-cell lymphoma. European Journal of Immunology, DOI: 10.1002/eji.201445375
As German Research Center for Environmental Health, Helmholtz Zentrum München pursues the goal of developing personalized medical approaches for the prevention and therapy of major common diseases such as diabetes mellitus and lung diseases. To achieve this, it investigates the interaction of genetics, environmental factors and lifestyle. The Helmholtz Zentrum München has about 2,300 staff members and is headquartered in Neuherberg in the north of Munich. Helmholtz Zentrum München is a member of the Helmholtz Association, a community of 18 scientific-technical and medical-biological research centers with a total of about 37,000 staff members.
The Institute of Molecular Immunology (IMI) performs application-oriented basic research at the interface of immunology, oncology and molecular biology. The objectives of the Institute are to elucidate the basic mechanisms of the immune system, to understand the pathogenesis of immunologically mediated diseases and to directly transfer insights gained in basic research into clinical applications. The Institute focuses on developing new personalized treatment strategies for the targeted modulation of the immune system.
Contact for the media: Department of Communication, Helmholtz Zentrum München - German Research Center for Environmental Health (GmbH), Ingolstädter Landstr. 1, 85764 Neuherberg - Phone: +49 89-3187-2238 - Fax: +49 89 3187 3324 - E-mail: presse@helmholtz-muenchen.de
Scientific contact at Helmholtz Zentrum München: Prof. Dr. med. Ralph Mocikat, Helmholtz Zentrum München - Deutsches Forschungszentrum für Gesundheit und Umwelt (GmbH), Institute of Molecular Immunology, Marchioninistr. 25, 81377 München - Phone: +49 89 3187 1302 - E-mail: Mocikat@helmholtz-muenchen.de
Journal
European Journal of Immunology