Center for Molecular Medicine Cologne

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

Understanding the impact of the lymphoid microenvironment in B cell malignancies by single-cell analysis


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.

Previous Work

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).

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                                                                                                                                                                                          • Kohlhas V, Hallek M*, Nguyen PH*.: Constitutive activation of Lyn kinase enhances BCR responsiveness, but not the development of CLL in Eµ-TCL1 mice. Blood Adv. 2020 Dec 22;4(24):6106-6116. doi: 10.1182/bloodadvances.2020002584. PMID: 33351104
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                                                                                                                                                                                          • Hansen HP, Paes Leme AF, and Hallek M (2020). Role of ADAM10 as a CD30 Sheddase in Classical Hodgkin Lymphoma. Front Immunol 11, 398.
                                                                                                                                                                                          • Di Cristanziano V, Meyer-Schwickerath C, Eberhardt KA, Rybniker J, Heger E, Knops E, Hallek M, Klein F, Holtick U, and Jung N (2020). Detection of SARS-CoV-2 viremia before onset of COVID-19 symptoms in an allo-transplanted patient with acute leukemia. Bone marrow transplantation 10.1038/s41409-020-01059-y.
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                                                                                                                                                                                          Prof. Dr. Michael Hallek CMMC Cologne
                                                                                                                                                                                          Prof. Dr. Michael Hallek

                                                                                                                                                                                          Clinic I of Internal Medicine

                                                                                                                                                                                          CMMC - PI - A 04

                                                                                                                                                                                          Executive Board Member

                                                                                                                                                                                          Publications - Michael Hallek

                                                                                                                                                                                          Link to PubMed

                                                                                                                                                                                          Dr. Phuong-Hien Nguyen CMMC Cologne
                                                                                                                                                                                          Dr. Phuong-Hien Nguyen

                                                                                                                                                                                          Clinic I for Internal Medicine

                                                                                                                                                                                          CMMC - PI - CAP 19

                                                                                                                                                                                          CMMC - Co-PI - A 04

                                                                                                                                                                                          Publications - Phuong-Hien Nguyen

                                                                                                                                                                                          Link to PubMed

                                                                                                                                                                                          Dr. Rocio Rebollido-Rios CMMC Cologne
                                                                                                                                                                                          Dr. Rocio Rebollido-Rios

                                                                                                                                                                                          Clinic I for Internal Medicine

                                                                                                                                                                                          CMMC - Co-PI - A 04

                                                                                                                                                                                          Publications - Rocio Rebollido-Rios

                                                                                                                                                                                          Link to PubMed

                                                                                                                                                                                          Figure 1
                                                                                                                                                                                          Group Members

                                                                                                                                                                                          Nicole Jörns, Admin. Assistenz
                                                                                                                                                                                          Dr. rer. nat. Phuong-Hien Nguyen, Co-PI
                                                                                                                                                                                          Dr. rer. nat. Rocio Rebollido-Rios, Co-PI
                                                                                                                                                                                          Dr. rer. nat. Oleg Fedorchenko
                                                                                                                                                                                          PD. Dr. rer. nat. Hinrich Hansen
                                                                                                                                                                                          Dr. nat. med. cand. Daniel Bachurski
                                                                                                                                                                                          Dr. rer. nat. cand. Maximilian Koch
                                                                                                                                                                                          Dr. rer. nat. cand. Sebastian Reinartz
                                                                                                                                                                                          Dr. rer. nat. cand. Viktoria Kohlhaas
                                                                                                                                                                                          Dr. rer. nat. cand. Thais Dolzany De Oliveira
                                                                                                                                                                                          Dr. rer. nat. cand. Maria José Fariña Morillas
                                                                                                                                                                                          Carina Folger, TA
                                                                                                                                                                                          Natascha Rosen, TA
                                                                                                                                                                                          Hedwig Göx, Medical Student
                                                                                                                                                                                          Lea Reemann, Medical Student
                                                                                                                                                                                          Alexander vom Stein, Medical Student
                                                                                                                                                                                          Max Bondarchenko, Master Student
                                                                                                                                                                                          Ludmila Lobastova, Master Student
                                                                                                                                                                                          Julia Saggau, Master Student