Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
Pansy, K.
Nuclear and chemokine receptors are involved in lymphomagenesis
PhD-Studium (Doctor of Philosophy); Humanmedizin; [ Dissertation ] Medizinische Universität Graz; 2024. pp. 140
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- Autor*innen der Med Uni Graz:
- Betreuer*innen:
- Deutsch Alexander
- Prokesch Andreas
- Sedej Simon
- Altmetrics:
- Abstract:
- In this first part of the thesis, the importance of studying the CXCR4/CXCL12 axis in diffuse large B cell lymphoma (DLBCL) is highlighted. In over 20 different cancers, the CXCR4-CXCL12 axis plays a crucial role in several key processes, including survival, tumor cell proliferation, migration metastasis, and invasion. However, research on the interplay of CXCR4 and CXCL12 in DLBCL is limited and inconsistent. To close this gap, we conducted a comprehensive study of the CXCR4-CXCL12 axis in our cohort of DLBCL patients. Additionally, we examined the impact of CXCR4 antagonists on lymphoma cell lines in vitro. In our study of DLBCL, we discovered a remarkable 140-fold upregulation in CXCR4 expression when compared to non-neoplastic controls. Moreover, elevated CXCR4 expression correlated with unfavorable clinical outcomes. Analysis of corresponding bone marrow biopsies revealed a correlation between CXCL12 expression and lymphoma infiltration rate. Further, we found a decrease in CXCR4 expression following treatment-induced remission of bone marrow involvement. In addition, we evaluated the effects of three CXCR4 antagonists in vitro: AMD3100 (Plerixafor), AMD070 (Mavorixafor), and WKI-a niacin derivative of AMD070 synthesized in our study. Notably, WK1 exhibited more potent pro-apoptotic effects compared to AMD070, inducing the expression of pro-apoptotic genes in CXCR4+ lymphoma cells. Interestingly, WK1 treatment led to decreased expression of genes associated with the ERK1/2, JNK, and NF-κB/BCR pathways. In summary, our findings indicate that the CXCR4-CXCL12 axis plays a substantial role in the development of DLBCL and presents a hopeful avenue for therapeutic intervention in aggressive lymphomas. The second part of the thesis investigated the effect of Nr4a1 loss/deficiency on the tumor microenvironment (TME) and the immune response in a lymphoma mouse model. Transplantation of lymphoma cells with Nr4a1 loss into immunocompetent C57BL/6 wild-type mice resulted in increased splenic malignant B cell infiltration, decreased CD3+ T cell infiltration including subtypes of CD4+ T cells and CD8+ T cells, and an increased M2 macrophages- and Tregs-content, indicating immunosuppression and an immune cell depleted TME. Furthermore, a higher content of CD3+ T cells co-expressed of several immune checkpoint proteins in mice transplanted with lymphoma cells with Nr4a1 loss indicated an immunodepleted, exhausted TME. Co-culture assays revealed a decrease in T cell-mediated lymphoma cell lysis in the absence of Nr4a1, a phenomenon partially alleviated by Ctla4-/- OT-1 CD8+ T cells. These findings suggest Nr4a1's involvement in modulating T cell functionality. Nr4a1-deficiency resulted in increased phosphorylation of several kinases related with signaling pathways implicated in cell growth, apoptosis, and immune regulation. Collectively, our findings emphasize the immunoregulatory role of Nr4a1 in shaping the TME and immune checkpoint regulation in murine lymphomas.