5 research outputs found

    Tyrosine kinases as therapeutic targets and their effect on the tumour microenvironment in oncogene-driven non-small-cell lung cancer

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    Lung cancer represents the most prevalent type of cancer and is responsible for the highest number of cancer-related deaths worldwide. Approximately 80 % of patients are non-small-cell lung cancer (NSCLC) cases. These can be further subcategorised depending on the histological and molecular composition of tumours. Oncogene-dependent NSCLC comprise a major subtype of NSCLC that harbours oncogenic driver mutations, for example in the epidermal growth factor receptor tyrosine kinase. These mutations induce aberrant activation of cell signalling, thus facilitating uncontrolled cell growth and tumorigenesis. Targeted therapy represents one essential treatment strategy that is well-established in the clinic for oncogene-driven NSCLC, for example in the form of tyrosine kinase inhibitors. Other therapy approaches, such as anti-angiogenic compounds, aim to modulate the tumour microenvironment (TME) to become less advantageous to tumour cells, thus inhibiting cancer progression. Unfortunately, highly adaptive tumour cells and the dynamic nature of the TME limit the benefits of targeted therapy due to the emergence of resistance mechanisms or suppression of immune response. Therefore, it is essential to elucidate the effects of targeted therapy on the TME to increase our understanding of the underlying mechanisms responsible for the escape of immunosurveillance and tumour progression. This thesis investigated the impact of targeted therapy on cancer cells and the TME in oncogene-driven NSCLC and evaluated the remaining difficulties associated with this therapy approach, which illustrate the need for optimisation of existing therapy options or development of alternative treatment strategies

    Ubiquitination and SUMOylation in Telomere Maintenance and Dysfunction

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    Telomeres are essential nucleoprotein structures at linear chromosomes that maintain genome integrity by protecting chromosome ends from being recognized and processed as damaged DNA. In addition, they limit the cell’s proliferative capacity, as progressive loss of telomeric DNA during successive rounds of cell division eventually causes a state of telomere dysfunction that prevents further cell division. When telomeres become critically short, the cell elicits a DNA damage response resulting in senescence, apoptosis or genomic instability, thereby impacting on aging and tumorigenesis. Over the past years substantial progress has been made in understanding the role of post-translational modifications in telomere-related processes, including telomere maintenance, replication and dysfunction. This review will focus on recent findings that establish an essential role for ubiquitination and SUMOylation at telomeres

    EGFR Inhibition Strongly Modulates the Tumour Immune Microenvironment in EGFR-Driven Non-Small-Cell Lung Cancer

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    EGFR-driven non-small-cell lung cancer (NSCLC) patients are currently treated with TKIs targeting EGFR, such as erlotinib or osimertinib. Despite a promising initial response to TKI treatment, most patients gain resistance to oncogene-targeted therapy, and tumours progress. With the development of inhibitors against immune checkpoints, such as PD-1, that mediate an immunosuppressive microenvironment, immunotherapy approaches attempt to restore a proinflammatory immune response in tumours. However, this strategy has shown only limited benefits in EGFR-driven NSCLC. Approaches combining EGFR inhibition with immunotherapy to stimulate the immune response and overcome resistance to therapy have been limited due to insufficient understanding about the effect of EGFR-targeting treatment on the immune cells in the TME. Here, we investigate the impact of EGFR inhibition by erlotinib on the TME and its effect on the antitumour response of the immune cell infiltrate. For this purpose, we used a transgenic conditional mouse model to study the immunological profile in EGFR-driven NSCLC tumours. We found that EGFR inhibition mediated a higher infiltration of immune cells and increased local proliferation of T-cells in the tumours. Moreover, inhibiting EGFR signalling led to increased activation of immune cells in the TME. Most strikingly, combined simultaneous blockade of EGFR and anti-PD-1 (aPD-1) enhanced tumour treatment response in a transgenic mouse model of EGFR-driven NSCLC. Thus, our findings show that EGFR inhibition promotes an active and proinflammatory immune cell infiltrate in the TME while improving response to immune checkpoint inhibitors in EGFR-driven NSCLC

    Tripartite antigen-agnostic combination immunotherapy cures established poorly immunogenic tumors

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    Background Single-agent immunotherapy has shown remarkable efficacy in selected cancer entities and individual patients. However, most patients fail to respond. This is likely due to diverse immunosuppressive mechanisms acting in a concerted way to suppress the host anti-tumor immune response. Combination immunotherapy approaches that are effective in such poorly immunogenic tumors mostly rely on precise knowledge of antigenic determinants on tumor cells. Creating an antigen-agnostic combination immunotherapy that is effective in poorly immunogenic tumors for which an antigenic determinant is not known is a major challenge. Methods We use multiple cell line and poorly immunogenic syngeneic, autochthonous, and autologous mouse models to evaluate the efficacy of a novel combination immunotherapy named tripartite immunotherapy (TRI-IT). To elucidate TRI-ITs mechanism of action we use immune cell depletions and comprehensive tumor and immune infiltrate characterization by flow cytometry, RNA sequencing and diverse functional assays. Results We show that combined adoptive cellular therapy (ACT) with lymphokine-activated killer cells, cytokine-induced killer cells, V gamma 9V delta 2-T-cells (gamma delta-T-cells) and T-cells enriched for tumor recognition (CTLs) display synergistic antitumor effects, which are further enhanced by cotreatment with anti-PD1 antibodies. Most strikingly, the full TRI-IT protocol, a combination of this ACT with anti-PD1 antibodies, local immunotherapy of agonists against toll-like receptor 3, 7 and 9 and pre-ACT lymphodepletion, eradicates and induces durable anti-tumor immunity in a variety of poorly immunogenic syngeneic, autochthonous, as well as autologous humanized patient-derived models. Mechanistically, we show that TRI-IT coactivates adaptive cellular and humoral, as well as innate antitumor immune responses to mediate its antitumor effect without inducing off-target toxicity. Conclusions Overall, TRI-IT is a novel, highly effective, antigen-agnostic, non-toxic combination immunotherapy. In this study, comprehensive insights into its preclinical efficacy, even in poorly immunogenic tumors, and mode of action are given, so that translation into clinical trials is the next step

    Inhibition of Tumor VEGFR2 Induces Serine 897 EphA2-Dependent Tumor Cell Invasion and Metastasis in NSCLC

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    Anti-angiogenic treatment targeting vascular endothelial growth factor (VEGF)-VEGFR2 signaling has shown limited efficacy in lung cancer patients. Here, we demonstrate that inhibition of VEGFR2 in tumor cells, expressed in similar to 20% of non-squamous non-small cell lung cancer (NSCLC) patients, leads to a pro-invasive phenotype. Drug-induced inhibition of tumor VEGFR2 interferes with the formation of the EphA2/VEGFR2 heterocomplex, thereby allowing RSK to interact with Serine 897 of EphA2. Inhibition of RSK decreases phosphorylation of Serine 897 EphA2. Selective genetic modeling of Serine 897 of EphA2 or inhibition of EphA2 abrogates the formation of metastases in vivo upon VEGFR2 inhibition. In summary, these findings demonstrate that VEGFR2-targeted therapy conditions VEGFR2-positive NSCLC to Serine 897 EphA2-dependent aggressive tumor growth and metastasis. These data shed light on the molecular mechanisms explaining the limited efficacy of VEGFR2-targeted anti-angiogenic treatment in lung cancer patients
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