Hallek, Michael | Nguyen, Phuong-Hien | Rebollido-Rios, Rocio - A 04

The application of targeted therapy and immunotherapy has significantly shifted cancer treatment towards a chemotherapy-free future. However, the emergence of resistance and the relatively low responsive rate remain the major challenges in these therapeutic options.

Based on the premise that the tumor microenvironment has a significant impact on cancer resistance to therapy, results from this project can be useful to design improved treatment regime for B cell malignancies.

Small molecule inhibitors targeting tyrosine kinases and immunotherapies including immune checkpoint blockade have tremendously improved the treatment of B lymphoid malignancies. Recently, increasing evidence emerged showing that the efficacy of these inhibitors depends not only on the inhibition of B cell-autonomous functions, but also by affecting several cell types in the tumor micrenvironment (TME). Using genetically engineered mouse models, we have discovered an unexpected, potent role of Lyn kinase for the formation of a pro-malignant lymphoid environment.

Moreover, we also observed a potential function of the immune checkpoint ligands in the TME contributing to lymphoma cell growth. Our preliminary analysis of the murine lymphoid organs revealed striking differences in the immune cell composition of the knockout mice compared to wild type counterpart, indicating a substantial contribution of these molecules in shaping a tumor-supportive niche. Therefore, the central aim of this project is to provide mechanistic insights into the highly complex and dynamic interactions between malignant cells and their TME, with single-cell analysis as the central technology.

Using the different knockout mouse lines with distinct defects in the immune microenvironment, we will develop bioinformatic framework for identification of the cellular composition and comparison of the immune transcriptional landscape in different disease stages, thereby providing a deeper understanding of the dialog that malignant cells and the TME can adopt during B cell lymphoma development.

In recent years, tremendous advances regarding the therapy of B lymphoid malignancies have been made with the development of small molecule kinase inhibitors targeting the B cell receptor (BCR)-associated kinases. Strikingly,increasing evidence emerged showing that the efficacy of these inhibitors depends not only on the inhibition of B cell-autonomous functions, but also by affecting several cell types in the TME.

This is strongly supported by clinical observations, because CLL patients treated with these kinase inhibitors showed a long-lasting lymphocytosis following the rapid decrease of lymphadenopathy, indicating that leukemic cells lose their contact to the TME and undergo a relocation from lymphoid homing organs to the periphery (Figure 1).