Studying CLL-immune interactions

Tumour cells and immune cells interact with each other and can inhibit or promote their growth. Within a tumour, not all tumour cells are the same, but can have different properties, e.g. DNA mutations or proteins. All cancer cells with the same properties are called a tumour clone and may have a growth advantage or disadvantage over other tumour clones. This may be due to the fact that these changes in the cancer cells are recognized as harmful by the body`s own immune cells which then eliminate the cancer cells. However, it is also possible that a mutation has an advantage for the cancer cell, e.g. because the mutation affects a gene that is important for the activation of immune cells, rendering them inactive. Thus, the tumour clone can proliferate and is not eliminated by the immune system. Tumour cells can use various mechanisms to evade detection by immune cells. They can do this either by "hiding" from the immune system or by suppressing the immune cells. Tumour clones that successfully use such a mechanism have an evolutionary advantage over other tumour cells. Such a tumour clone will grow and defend itself optimally against killing by immune cells. A change in the clonal composition of the tumour is therefore also reflected in the immune response, which is responsible for the outgrowth of certain clones. In this project, this clonal tumour evolution and the changes in immune cells (especially T cells) are investigated. We will analyse how suppression and escape from the immune response works and which properties of tumour cells are responsible for the influence on T cells. With this knowledge, new treatment approaches, which aim at making the tumour more visible to immune cells or activating the T- cells, can be developed.

Immunoediting describes the dynamic interaction between cancer cells and the immune system, in which cancer cells ultimately evade the body's own immune defenses, silencing the immune cells - especially T cells - resulting in unhindered growth of cancer cells. Although immune checkpoint therapies can successfully reactivate the immune system in some cancers and thus bring patients into remission, many cancers, including chronic lymphocytic leukemia (CLL), do not respond. For improved therapies, it is important to understand why in many cases the immune system cannot be reactivated to fight cancer. With the help of this research project, we were able to address this question in detail. Using appropriate mouse models, we were able to show that after the development of CLL, the non-CLL-specific T cells were also silenced, which is dependent on the presence of (tumor-)antigen-specific T cells. Transcriptome analyses confirmed the exhaustion phenotype of non-CLL-specific T cells in this model. Our results suggest that in the CLL mouse model, a significant proportion of non-CLL-specific T cells are exhausted during disease progression due to a bystander effect. In this context, using combined amplicon/antibody/scRNAseq methods, we were able to characterize the T cell changes that manifest in the course of CLL disease depending on clinical progression at the single cell level in terms of clonality and gene expression. Furthermore, we were able to show that the antigen receptor - i.e. the specificity - of CLL cells influences the severity of the disease and of associated lymphadenopathies and that an increased mTor-mediated signaling cascade may be associated with therapy resistance of CLL. Finally, the funding also allowed the establishment of several bioinformatic analysis platforms. This made it possible to investigate i) the tumor microenvironment and ii) the tumor-immune interaction and iii) clonal tumor evolution using single-cell imaging mass cytometry and various single-cell DNA/RNA sequencing methods (NGS). The knowledge gained from the project has important implications for the understanding of immunoediting, cancer-immune crosstalk and the further development of immunotherapies as a promising cancer therapy for patients.