The importance of ectonucleotidase activity for the function of B cells and their relevance for immunotherapy in patients with head and neck cancer

• Applicant: Professor Dr. Patrick Johannes Schuler
• Subject Area: Otolaryngology, Phoniatrics and Audiology ; Hematology, Oncology
• Term: from 2014 to 2018
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 264624709

Despite the recent advances in the field of surgery and radio-chemotherapy the survival rate of patients with head and neck squamous cell carcinoma (HNSCC) has not improved during the last decades. This observation supports the need for the development of new, improved therapeutic approaches. Besides the rapid tumor growth, the high rate of metastasis and the strong suppression of the host immune system are malignant hallmarks of HNSCC. The tumor induced immune escape mechanism involves a weak immunity of tumor cells, resistance against radio-chemotherapy and dysfunction of various immune cell populations. In the past, immune escape was mainly linked to known immune suppressive cell populations, e.g. regulatory T cells (Treg), mesenchymal stem cells (MSC), myeloid derived suppressor cells (MDSC), and immune suppressive exosomes. All of the above listed cell populations have in common, that they are also found at a low frequency in healthy humans, where they play an important role in the maintenance of peripheral selftolerance. Previous immunotherapeutic approaches in patients with HNSCC have been mostly unsuccessful, which was attributed to the increased presence of immune suppressive cell populations. Especially for Treg, MSC and exosomes we were able to demonstrate a considerable role in the production of exogenous adenosine, which is a strongly immunosuppressive purine nucleoside. It is generated by the activity of the ectonucleotidases CD39 and CD73, which are expressed on the surface of various immune cells. In our last publication, we demonstrated that B cells have a much greater potency for adenosine production than other cell populations mentioned above. This gives evidence for additional regulatory functions of B cells, which could have strong impact especially in the immune suppressive tumor milieu of HNSCC patients. Until now, this has not been sufficiently investigated. Based on our previous experiments, the following hypothesis is proposed: The production of exogenous adenosine is an immunosuppressive mechanism, which is also utilized by human B cells. Especially in HNSCC patients with local metastasis, the high frequency of B cells in the lymph nodes can account for additional immune suppression und progressive tumor growth. Our proposed studies could identify a group of HNSCC patients, which profit from a selective modulation of adenosine production by B cells.

• DFG Programme: Research Grants