Dokument: Novel therapeutic strategies and modulators of anti-tumor immunity in melanoma
| Titel: | Novel therapeutic strategies and modulators of anti-tumor immunity in melanoma | |||||||
| Weiterer Titel: | Neue therapeutische Strategien und Modulatoren der Anti-Tumor-Immunität bei Melanomen | |||||||
| URL für Lesezeichen: | https://docserv.uni-duesseldorf.de/servlets/DocumentServlet?id=57661 | |||||||
| URN (NBN): | urn:nbn:de:hbz:061-20221018-091450-7 | |||||||
| Kollektion: | Dissertationen | |||||||
| Sprache: | Englisch | |||||||
| Dokumententyp: | Wissenschaftliche Abschlussarbeiten » Dissertation | |||||||
| Medientyp: | Text | |||||||
| Autor: | Liu, Wei [Autor] | |||||||
| Dateien: |
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| Beitragende: | Prof. Dr. med. Lang, Philipp [Gutachter] Prof. Dr. med. Homey, Bernhard [Gutachter] | |||||||
| Dewey Dezimal-Klassifikation: | 600 Technik, Medizin, angewandte Wissenschaften » 610 Medizin und Gesundheit | |||||||
| Beschreibung: | Melanoma accounts for a large proportion of cancer-related deaths. New therapies are urgently needed in melanoma, particularly in late-stage patients not responsive to immunotherapies and kinase inhibitors. In the first section of the dissertation, we conducted a pharmacologic screen composed of the NIH Clinical Collection (NCC) of 770 small molecules, FDA-approved or which have been previously used in human clinical trials to identify novel anti-melanoma agents. Each molecule was screened in the murine B16.F10 cell line and its half maximal inhibitory concentrations (IC50) was determined. Amongst the compounds whose IC50 values were in the low micromolar range, Tegaserod (TM), a serotonin receptor 4 (HTR4) agonist, validated successfully in secondary screening approaches with BRAF WT and BRAFV600E human melanoma cell lines. The anti-cancer efficacy of TM was further evaluated in in vitro and in vivo studies. TM induced apoptosis in a dose and time dependent manner in the B16.F10 murine melanoma cell line as well as several human melanoma cell lines. In vivo, TM was well-tolerated and anti-tumoral effects were validated in a syngeneic melanoma model testing primary tumor growth and metastasis. Furthermore, TM strongly synergized with the standard of care BRAFV600E targeting Vemurafenib in human melanoma cell lines with this mutation. Mechanistically, TM inhibited PI3K/Akt/mTOR signaling converging on ribosomal protein S6 (S6) in vitro and in vivo. Inhibition of the PI3K/Akt/mTOR pathway was likely responsible for TM’s pro-apoptotic effects and anti-metastatic effects in melanoma cell lines. Pharmacological inhibition of the pathway using specific inhibitors recapitulated the apoptotic phenotype confirming the sensitivity of melanoma cells to PI3K/Akt/mTOR pathway perturbation. Taken together, we have identified a drug with anti-melanoma activity that has the potential to be combined with the standard of care agent Vemurafenib and Cobimetinib in both BRAFV600E and BRAF WT melanoma.
On the other hand, many new therapies, such as cytokine, vaccine, and antibody-based therapies, rely on exploiting the immune system to fight tumors. In solid tumors, the tumor microenvironment (TME) is a complex milieu composed of infiltrating immune cells, stromal cells, vasculature, and tumor cells whose composition is shaped by the different factors including cytokines, chemokines, growth factors and metabolites within it. Due to the TME’s inherent complexity, further research is needed to understand the contribution of the different components including cytokines within it. The second portion of the dissertation focuses on dissecting the effects of the cytokine B cell activating factor (BAFF) on anti-tumoral immunity in melanoma. While the role of BAFF in the survival of B cells and as a prognostic factor in autoimmune diseases and hematological malignancies is well known, it is unclear how BAFF impacts solid tumor growth. We generated a BAFF-overexpressing B16.F10.gp33 (BAFF) system in melanoma cells. The expression of BAFF inhibits tumor growth. Characterization of BAFF and control tumors indicated increased tumor apoptosis and a decrease in the expression of immunosuppressive factors including Programmed Cell Death 1 Ligand 1 (PD-L1) in BAFF tumors. Not only did BAFF tumors have lower numbers of myeloid infiltrates, but the PD-L1 expression on infiltrating monocytes in BAFF tumors was also decreased. Depletion of monocytes as well as treatment with an anti-PD-L1 antibody confirmed the functional dependence of the difference in tumor growth between BAFF and control tumors on monocytes and PD-L1 expression. RNA-Seq analysis of monocytes isolated from BAFF and control tumors further confirmed that monocytes isolated from BAFF tumors where characterized by a decreased exhaustive phenotype and enriched for in genes activating adaptive immune responses and NF-κB signaling. Using knockout mice and depletion antibodies, the phenotype was found to be influenced by NK cells. In summary, we have shown that BAFF impacts tumor growth through decreased tumor infiltrating monocytes and activated NK cells. | |||||||
| Lizenz: |  Urheberrechtsschutz | |||||||
| Fachbereich / Einrichtung: | Medizinische Fakultät » Institute » Institut für Molekulare Medizin | |||||||
| Dokument erstellt am: | 18.10.2022 | |||||||
| Dateien geändert am: | 18.10.2022 | |||||||
| Promotionsantrag am: | 04.05.2021 | |||||||
| Datum der Promotion: | 30.09.2021 |
