Treatment for B cell malignancies has shifted towards a chemo-free regiment with the combination of targeted therapy and/or immunotherapy. However, resistance to these therapeutics has emerged and new complementary options are still urgently needed for these cases.

Regulation of T cell activity and restoration of T cell-mediated anti-tumor responses represent a prime research focus for immunotherapy. However, tumor cells can employ various mechanisms to evade anti-tumor immune responses, leading to the failure of cytotoxic T cells to efficiently proliferate and form immunologic synapses. The deregulated expression of diverse immune checkpoint molecules as well as co-stimulatory receptors have been described to modulate the activation of major T cell subsets. Moreover, the modulating effect of stromal cells on lymphoma development and T cell activity has been increasingly acknowledged. Stromal cells not only contribute to tumor growth via the interdependent generation of a nurturing tumor niche, but also adopt a number of other immunosuppressive mechanisms to modulate immune responses resulting in an enhanced immune tolerance to the tumor.

The main goal of this project is to understand the complex regulation of T cell immunity by both the stroma and lymphoma cells to develop new therapeutic combinations. Particularly, regimens combining targeted- and immunotherapies will be tested in different in vitro and in vivo models.

Clinical Relevance

The modulation of anti-lymphoma T cell activity is not fully elucidated. Understanding the multifaceted regulation of T cell responses by both malignant cells and the stromal microenvironment will provide more insights into the effectiveness as well as vulnerability of T cell-based immunotherapy for B cell lymphoma. Ultimately, our project seek to develop preclinically complementary therapies against lymphoma hindering immune-suppressions caused by stromal deregulations and T cell exhaustion.

Approach

Explore the molecular mechanisms underlying stroma-induced remodeling of T cell immunity and anti-tumor response.
Elucidate the adaptation of lymphoma cells during immunotherapy and their impacts on T cell phenotype and activity.
Test the potential of combined immunotherapy for improved B cell lymphoma treatment.

Figure 1

CMMC Research — Fig. 1: (Nguyen et al., Leukemia 2019): Cellular components of the lymphoma microenvironment interact with tumor cells and with each other in a complex multidirectional manner to promote malignant progression.

Figure 2

Fig. 2: (Images acquired with Incucyte® Live-Cell Analysis Systems by Liudmila Lobastova): Primary leukemic B cells (red) undergo apoptosis (green) after contact with a T cell.

Figure 3

Fig. 3: (Images acquired with Hyperion™ Imaging System by Daniel Bachurski): Lymph nodes (LN) from chronic lymphocytic leukemia (CLL) patients show the typical disappearance of the architecture compared to healthy controls, accompanied by a differential distribution of B cells and bystander cells (Yellow: CD79A+ B cells; Magenta: CD8A+ T cells; Cyan: Vimentin+ stromal cells).

Affiliations - Phuong-Hien Nguyen

CRC / SFB 1530
Center for Integrated Oncology
CRU 286 - Exploiting defects in the DNA damage response for the development of novel, targeted CLL therapy

Affiliations - Alessandro Annibaldi

CMMC Center for Molecular Medicine

Publications generated during 1/2023-12/2025 with CMMC affiliation

2024 (up to June)

Iqbal S, Schneider TK, Truong TT, Ulrich-Muller R, Nguyen PH, Ilyas S, and Mathur S (2024). Carriers for hydrophobic drug molecules: lipid-coated hollow mesoporous silica particles, and the influence of shape and size on encapsulation efficiency. Nanoscale16, 11274-11289. doi:10.1039/d4nr01420k.
Jestrabek H, Kohlhas V, Hallek M, and Nguyen PH (2024). Impact of leukemia-associated macrophages on the progression and therapy response of chronic lymphocytic leukemia. Leuk Res143, 107531. doi:10.1016/j.leukres.2024.107531.
Kath J, Franke C, Drosdek V, Du W, Glaser V, Fuster-Garcia C, Stein M, Zittel T, Schulenberg S, Porter CE, Andersch L, Kunkele A, Alcaniz J, Hoffmann J, Abken H, Abou-El-Enein M, Pruss A, Suzuki M, Cathomen T, Stripecke R, Volk HD, Reinke P, Schmueck-Henneresse M, and Wagner DL (2024). Integration of zeta-deficient CARs into the CD3zeta gene conveys potent cytotoxicity in T and NK cells. Blood143, 2599-2611. doi:10.1182/blood.2023020973.

2023

Braun T, Pruene A, Darguzyte M, Vom Stein AF, Nguyen PH, Wagner DL, Kath J, Roig-Merino A, Heuser M, Riehm LL, Schneider A, Awerkiew S, Talbot SR, Bleich A, Figueiredo C, Bornhauser M, and Stripecke R (2023). Non-viral TRAC-knocked-in CD19(KI)CAR-T and gp350(KI)CAR-T cells tested against Burkitt lymphomas with type 1 or 2 EBV infection: In vivo cellular dynamics and potency. Front Immunol 14, 1086433. doi:10.3389/fimmu.2023.1086433.
de Oliveira TD, Vom Stein A, Rebollido-Rios R, Lobastova L, Lettau M, Janssen O, Wagle P, Nguyen PH, Hallek M, and Hansen HP (2023). Stromal cells support the survival of human primary chronic lymphocytic leukemia (CLL) cells through Lyn-driven extracellular vesicles. Front Med (Lausanne) 9, 1059028. doi:10.3389/fmed.2022.1059028.
Flumann R, Hansen J, Pelzer BW, Nieper P, Lohmann T, Kisis I, Riet T, Kohlhas V, Nguyen PH, Peifer M, Abedpour N, Bosco G, Thomas RK, Kochanek M, Knufer J, Jonigkeit L, Beleggia F, Holzem A, Buttner R, Lohneis P, Meinel J, Ortmann M, Persigehl T, Hallek M, Calado DP, Chmielewski M, Klein S, Gothert JR, Chapuy B, Zevnik B, Wunderlich FT, von Tresckow B, Jachimowicz RD, Melnick AM, Reinhardt HC, and Knittel G (2023). Distinct Genetically Determined Origins of Myd88/BCL2-Driven Aggressive Lymphoma Rationalize Targeted Therapeutic Intervention Strategies. Blood Cancer Discov 4, 78-97. doi:10.1158/2643-3230.BCD-22-0007.
Theobald SJ, Fiestas E, Schneider A, Ostermann B, Danisch S, von Kaisenberg C, Rybniker J, Hammerschmidt W, Zeidler R, and Stripecke R (2023). Fully Human Herpesvirus-Specific Neutralizing IgG Antibodies Generated by EBV Immortalization of Splenocytes-Derived from Immunized Humanized Mice. Cells 13. doi:10.3390/cells13010020.
Vom Stein AF, Hallek M, and Nguyen PH (2023). Role of the tumor microenvironment in CLL pathogenesis. Semin Hematol. doi:10.1053/j.seminhematol.2023.12.004.
Vom Stein AF, Rebollido-Rios R, Lukas A, Koch M, von Lom A, Reinartz S, Bachurski D, Rose F, Bozek K, Abdallah AT, Kohlhas V, Saggau J, Zolzer R, Zhao Y, Bruns C, Brockelmann PJ, Lohneis P, Buttner R, Haupl B, Oellerich T, Nguyen PH, and Hallek M (2023). LYN kinase programs stromal fibroblasts to facilitate leukemic survival via regulation of c-JUN and THBS1. Nat Commun 14, 1330. doi:10.1038/s41467-023-36824-2.

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Nguyen, Phuong-Hien | Renata Stripecke | Alessandro Annibaldi - A 09

Understanding the multifaceted regulation of T cell immunity in B cell lymphoma for improved immunotherapy

Dr. Phuong-Hien Nguyen

Prof. Dr. Renata Stripecke

Dr. Alessandro Annibaldi

Introduction