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Title
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Combined targeting of the epidermal growth factor receptor and the innate immune system : a novel therapeutic approach for the treatment of head and neck cancer
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Author
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Abstract
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| Head and neck squamous cell carcinomas (HNSCC) are a group of malignancies that despite preventative measures and advances in cancer treatments, have a detrimental impact on patients’ outcome and quality of life. Targeted therapies and immunotherapies, being at the forefront of personalized cancer medicine, aim to fulfil the dire need for effective treatment strategies. However, despite promising clinical results, the effectiveness of these modalities is severely limited due to the heterogeneous nature of HNSCC and the presence of multiple resistance and immune evasion mechanisms. In this dissertation, our goal was to investigate whether these shortcomings could be overcome through combined targeting of the epidermal growth factor receptor (EGFR) together with immunotherapeutic modalities that focus on reinvigorating natural killer (NK) cells. We showed that treatment of different HNSCC cell lines with the anti-EGFR antibody, cetuximab, in co-culture with NK cells was capable of inducing antibody-dependent cellular cytotoxicity (ADCC) independent of basal EGFR levels. Characterization of the immune signature of HNSCC patients indicated an inflamed tumor environment. NK cell presence was largely restricted to peritumoral stroma but strongly associated with improved survival. Increased expression of CD276 and CD155 were identified as negative prognostic factors and regarded as potential novel immunotherapeutic targets. Combined with the idea that chemo- and targeted therapies may influence the immune landscape, we investigated the immunomodulatory effects of cetuximab in vitro. Differences in expression of immune checkpoint ligands between various HNSCC cell lines based on their cetuximab sensitivity were limited in size but observable. Based on the overall high expression of CD155, CD276 and CD47 across all cell lines, these were suggested as interesting targets for therapeutic intervention. Investigating the complimentary receptors of these ligands on NK cells showed a clear presence of TIGIT and DNAM-1 on both healthy and patient-derived NK cells. Thus, the TIGIT/CD155-signaling axis was interrupted as a means to enhance the antitumor activity of NK cells towards our panel of HNSCC cell lines. Combined targeting of CD155 with cetuximab synergistically enhanced the antitumor activity of NK cells compared to single agent treatments in all cell lines, especially the intrinsically resistant cells. In conclusion, the data presented in this dissertation support the rationale for combining cetuximab with CD155 inhibition to enhance the NK cell antitumor activity and overcome cetuximab resistance. |
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Language
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English
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Publication
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Antwerpen
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Universiteit Antwerpen, Faculteit Geneeskunde en Gezondheidswetenschappen
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2022
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Volume/pages
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225 p.
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Note
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Lardon, Filip [Supervisor]
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Wouters, An [Supervisor]
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De Waele, Jorrit [Supervisor]
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Full text (open access)
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