Abstract
Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer type worldwide, with a majority of the patients progressing towards recurrent/metastatic HNSCC with limited treatment options. Despite the high natural killer (NK) cell infiltration, the efficiency of newly developed adoptive cellular therapies in clinical trials is limited. Therefore, I hypothesize that HNSCC cells secrete immunosuppressive metabolites in the tumor microenvironment (TME), exaggerated by the high level of hypoxia, inducing evasion to NK cells. Using physiologic and conditioned media at different oxygen levels, metabolic alterations in the TME are characterized by gas chromatography-mass spectrometry, providing high-value candidate metabolites that are later evaluated in a high-throughput screen to determine their effect on the NK cell killing capacity. Intracellular metabolic and functional changes of NK cells induced by exposure to the interfering metabolites are identified together with phenotypic profiling. Using an orthotopic humanized mouse model, NK cell functionality is investigated after modification of the TME and restoration of NK cell cytotoxicity combined with standard-of-care HNSCC treatment is evaluated. Concluding, this project will obtain fundamental insights into the suppressive role of hypoxia-induced metabolites on NK cells and will provide valuable knowledge for adoptive cellular therapies in development.
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