Strategies to improve the efficacy of NK cells in targeting aggressive B-cell lymphomas

• Applicant: Professor Dr. Carsten Watzl
• Subject Area: Immunology ; Hematology, Oncology
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 538763765

The goal of this project is to investigate the mechanisms of B-cell lymphoma resistance to NK cell-mediated cellular cytotoxicity in order to propose solutions to circumvent them. We aim at proposing novel improved immunotherapeutic approaches for patients with aggressive lymphomas that relapse or are primarily refractory (r/r) to first line treatment based on the combination of an anti-CD20 monoclonal antibody (mAb) rituximab (RTX) plus chemotherapy (R-CHOP scheme). The clinical observations define this group as patients with particularly poor prognosis and unsatisfactory response to second line therapies. Many studies have demonstrated the emergence of phenotypic changes in the tumor cells exposed to RTX that may be responsible for this lack of success. Therefore, the more accurate understanding of the mechanisms of resistance to second-line therapies in order to optimize their use is still needed. In our preliminary experiments using well-established cellular models of RTX-resistance we observe that lymphoma cells acquire resistance to the cytotoxic activity of NK cells following long-time incubation with RTX. Importantly, RTX-resistant cells are less sensitive to the cytotoxicity of NK cells, despite never have been in contact with the latter. Moreover, the RTX-resistant cells are characterized with several phenotypic alterations that may be responsible for impaired efficacy of effector cells. Therefore, by deciphering the mechanisms by which lymphoma cells are killed by NK cells and through a detailed analysis of the factors influencing resistance to NK cells, we aim at proposing the prerequisites for successful NK-based immunotherapy for aggressive lymphoma patients. In the proposed project we will: 1. Evaluate the resistance to NK cells in mAbs-resistant cellular models. 2. Analyze the mechanisms of resistance to NK cells’ cytotoxicity and validate their importance in primary samples. 3. Design strategies to overcome resistance to NK cells. Besides proposing novel approaches, we believe that our analyses, combined with the preexisting studies on CAR T cells, will bring new knowledge on the requirements for designing effective cellular immunotherapies. The whole project will be realized in close collaboration between the Polish team with expertise in biology of malignant B cells and immunotherapy and the German team - the renowned experts in NK cell biology.

• DFG Programme: Research Grants
• International Connection: Poland
• Partner Organisation: Narodowe Centrum Nauki (NCN)
• Cooperation Partner: Dr. Malgorzata Bobrowicz