Characterization of the immune microenvironment in chronic lymphocytic leukemia with regard to recurrent genomic aberrations and identification of mechanisms of resistance towards novel treatment strategies mediated by the immune microenvironment

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Chronic lymphocytic leukemia (CLL) is the most common leukemia in the western world. From its variable clinical behavior it is obvious that CLL is not a homogeneous disease. Genomic aberrations and mutations have strong clinical impact, but up to now intrinsic defects alone cannot explain the heterogeneity to full extent. Extrinsic factors from the microenvironment induced by the malignant cell clone are likely to add on pathogenesis, clinical course and response to treatment. The central hypothesis of the proposed research project is that in CLL distinct disease subgroups defined by genomic variations induce different changes to their cellular microenvironment.Capacity of the CLL cells in general to induce functional changes in T cells has already been demonstrated. Those changes do probably lead to a more hospitable microenvironment with less activity of the host immune system against the malignant clone.Therefore, after a detailed genomic characterization of the sample pool the different cellular components of the tumor microenvironment will be characterized in regard to localization, function and their interaction with the CLL cells. Since common pathways in tumorigenesis are altered in CLL (TP53, ATM, c-MYC, NOTCH signaling, defects in the splicing machinery), transferability of the results to other tumor entities might be possible.Changes in the immune microenvironment are likely to influence response to treatment. A first example of genetically determined resistance to immunotherapy in CLL is the lack of benefit from the addition of Rituximab to chemotherapy in NOTCH1 mutated CLL cases. If intrinsic defects as underlying mechanism can be ruled out, the hypothesis will be that an impaired interaction between CLL cells and the toxicity mediating effector cells causes resistance.In general, CLL treatment is moving more and more towards targeted, chemotherapy-free regimens integrating environmental cells into the mechanism of action. Substances under investigation are novel monoclonal antibodies and chimeric antigen receptors (CARs) requiring functional effector cells and complement among other factors to induce tumor cell death. In addition, inhibitors of B cell receptor signaling, BCL2-inhibitors and immunomodulatoy agents have shown great potential as new treatment paradigms in CLL. All these agents are currently under investigation in clinical trials and first results show promising efficacy combined with favorable tolerability. Nonetheless, it becomes more and more apparent, that not all disease subgroups benefit to the same extent. With an increasing role of therapeutic strategies that implicate environmental immune cells, it is very likely that dysfunctions in the microenvironment add to resistance. The data from our proposed project could provide a valuable source to quickly screen for underlying mechanisms of treatment failure and find therapeutic strategies to overcome resistance.