Center for Molecular Medicine Cologne

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

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

Introduction

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).

Project Related Publications

  1. Fischer K, Al-Sawaf O, Bahlo J, Fink AM, Tandon M, Dixon M, Robrecht S, Warburton S, Humphrey K, Samoylova O, Liberati AM, Pinilla-Ibarz J, Opat S, Sivcheva L, Le Dû K, Fogliatto LM, Niemann CU, Weinkove R, Robinson S, Kipps TJ, Boettcher S, Tausch E, Humerickhouse R, Eichhorst B, Wendtner CM, Langerak AW, Kreuzer KA, Ritgen M, Goede V, Stilgenbauer S, Mobasher M, and Hallek, M. (2019). Venetoclax and Obinutuzumab in Patients with CLL and Coexisting Conditions. N Engl J Med. 380, 2225-2236.
  2. Nguyen P.H.*, Niesen E.*, and Hallek M.: New roles for B cell receptor associated kinases: when the B cell is not the target. Leukemia2019 Mar; 33(3):576-587
  3. Herling, C.D., Abedpour, N., Weiss, J., Schmitt, A., Jachimowicz, R.D., Merkel, O., Cartolano, M., Oberbeck, S., Mayer, P., Berg, V., Thomalla, D., Kutsch, N., Stiefelhagen, M., Cramer, P., Wendtner, C.M., Persigehl, T., Saleh, A., Altmuller, J., Nurnberg, P., Pallasch, C., Achter, V., Lang, U., Eichhorst, B., Castiglione, R., Schafer, S.C., Buttner, R., Kreuzer, K.A., Reinhardt, H.C., Hallek, M., Frenzel, L.P., and Peifer, M. (2018). Clonal dynamics towards the development of venetoclax resistance in chronic lymphocytic leukemia. Nat Commun 9, 727-730.
  4. Nguyen, P.H., Fedorchenko, O., Rosen, N., Koch, M., Barthel, R., Winarski, T., Florin, A., Wunderlich, F.T., Reinart, N., and Hallek, M. (2016). LYN Kinase in the Tumor Microenvironment Is Essential for the Progression of Chronic Lymphocytic Leukemia. Cancer Cell 30, 610-622.
  5. Landau, D.A., Tausch, E., Taylor-Weiner, A.N., Stewart, C., Reiter, J.G., Bahlo, J., Kluth, S., Bozic, I., Lawrence, M., Bottcher, S., Carter, S.L., Cibulskis, K., Mertens, D., Sougnez, C.L., Rosenberg, M., Hess, J.M., Edelmann, J., Kless, S., Kneba, M., Ritgen, M., Fink, A., Fischer, K., Gabriel, S., Lander, E.S., Nowak, M.A., Dohner, H., Hallek, M.,* Neuberg, D.,* Getz, G.,* Stilgenbauer, S.,* and Wu, C.J.* (2015). Mutations driving CLL and their evolution in progression and relapse. Nature 526, 525-530. *Joint senior authors
  6. Reinart, N., Nguyen, P.H., Boucas, J., Rosen, N., Kvasnicka, H.M., Heukamp, L., Rudolph, C., Ristovska, V., Velmans, T., Mueller, C., Reiners, K.S., von Strandmann, E.P., Krause, G., Montesinos-Rongen, M., Schlegelberger, B., Herling, M., Hallek, M., and Fingerle-Rowson, G. (2013). Delayed development of chronic lymphocytic leukemia in the absence of macrophage migration inhibitory factor. Blood  121, 812-821.
  7. Hallek, M., Fischer, K., Fingerle-Rowson, G., Fink, A.M., Busch, R., Mayer, J., Hensel, M., Hopfinger, G., Hess, G., von Grunhagen, U., Bergmann, M., Catalano, J., Zinzani, P.L., Caligaris-Cappio, F., Seymour, J.F., Berrebi, A., Jager, U., Cazin, B., Trneny, M., Westermann, A., Wendtner, C.M., Eichhorst, B.F., Staib, P., Buhler, A., Winkler, D., Zenz, T., Bottcher, S., Ritgen, M., Mendila, M., Kneba, M., Dohner, H., and Stilgenbauer, S. (2010). Addition of rituximab to fludarabine and cyclophosphamide in patients with chronic lymphocytic leukaemia: a randomised, open-label, phase 3 trial. Lancet 376, 1164-1174.
Prof. Dr. Michael Hallek CMMC Cologne
Prof. Dr. Michael Hallek

Dept. I of Internal Medicine / RG location - CECAD Building

Principal Investigator - A 04

Executive Board Member

+49 221 478 4400

+49 221 478 5455

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Kerpener Str. 62

50937 Cologne

http://innere1.uk-koeln.de/team

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Publications - Michael Hallek

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Dr. Hien Nguyen CMMC Cologne
Dr. Hien Nguyen

Dept. I for Internal Medicine / RG location - CECAD Building

Co-Principal Investigator - A 04

+49 221 478 84120

+49 221 478 32400

Dept. I for Internal Medicine / RG location - CECAD Building

Joseph-Stelzmann Str. 26

50931 Cologne

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Publications - Hien Nguyen

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

Dept. I for Internal Medicine / RG location - CECAD Building

Co-Principal Investigator - A 04

Dept. I for Internal Medicine / RG location - CECAD Building

Joseph-Stelzmann Str. 26

50931 Cologne

CMMC Profile Page

Curriculum Vitae (CV)

Publications on PubMed

Publications - Rocio Rebollido-Rios

Link to PubMed

Group Members

Hinrich Hansen
Oleg Fedorchenko
Daniel Bachurski
Yannick d'Hargues
Maximilian Koch
Sebastian Reinartz
Viktoria Kohlhas
Thais Dolzany De Oliveira
Maria Farina-Morillas

 

Figure 1