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.

Kinase inhibitors are now routinely used for treating hematological malignancies. The modulation of non-malignant bystander cells is not only an apparent off-target effect of these inhibitors, but also contributes importantly to the mechanisms of action of kinase inhibitors in B cell leukemia. Using genetically engineered mouse models, we have discovered an unexpected, potent role of Lyn kinase for the formation of a pro-malignant lymphoid environment. We could show that deletion of Lyn resulted in significantly reduced lymphoma burden in vivo using two validated transgenic mouse models for B cell tumors, which was due to the loss of Lyn and its substrate Btk in the tumor microenvironment (TME) rather than within the leukemic cells. Lyn was shown to have important functions in numerous hematopoietic cells of the myeloid lineage. Particularly, increasing evidence indicates that Lyn is involved in regulating the function of various cell types within the non-hematopoietic compartment. Using a comprehensive multi-omics profiling approach, we found that the presence of LYN kinase in the stromal microenvironment supports leukemic cell survival by shaping the cancer-associated-fibroblast (CAF)-like polarization of stromal cells and maintaining a tumor supportive extracellular matrix (ECM) composition. Deletion of LYN in stromal cells consistently decreased the capacity of stromal cells to support leukemic cell survival.

Our project provides mechanistic insights into the highly complex and dynamic interactions between malignant cells and their TME, with single-cell transcriptome as the central technology. Using the different knockout mouse lines with distinct defects in the immune microenvironment, we develop a bioinformatics framework to identify cellular populations and compare the immune transcriptional landscape at different disease stages, thereby providing a deeper understanding of the dialog that malignant cells and the TME can adopt during B cell lymphoma development. 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

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).