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, underscoring an unmet clinical need. The observation that HNSCC is one of the most inflamed and immune infiltrated tumor types, with an exceptionally high infiltration of natural killer (NK) cells, supports the potential of NK cells as a therapeutic agent for this indication. Importantly, immunometabolism is pivotal to immune responses, including for NK cells, yet, how the tumor microenvironment affects NK cell metabolism is largely unknown and identifying NK cell evasion mechanisms could unlock both current and new therapies for HNSCC.
We hypothesize that the deregulated metabolism of HNSCC cells is a pleiotropic hallmark in evasion to NK cells. We postulate that these metabolic resistance mechanisms are dual. On the one hand, metabolic reprogramming of HNSCC cells could mediate intracellular resistance to killing by NK cells. On the other hand, the metabolically deregulated HNSCC cells modify the metabolic composition of the tumor microenvironment, resulting in suppression of NK cells due to metabolite disbalance. This ultimately promotes immune evasion and jeopardizes survival of HNSCC patients. Unravelling these resistance mechanisms bear the potential to push NK cell therapies forward.
To this end, we will perform multi-omics analyses, target identification, genetic engineering and pharmacological targeting, 2D and 3D in vitro experiments, in silico validation and in vivo testing. First, we will elucidate the linchpins of intracellular metabolic pathways in HNSCC cell driving resistance to NK cell-killing by conducting a CRISPR knockout screen using a metabolism-focused library and the top targets will be validated using patient datasets and functional assays. Second, we will unravel the effect of extrinsic metabolites, secreted by HNSCC cells, on NK cell-mediated killing. The key metabolites responsible for reduced NK cellular killing capacity will be identified and validated correspondingly. Finally, the potential of metabolic interference of these targets to boost the next generation NK cell therapy for HNSCC, i.e. chimeric antigen receptor (CAR) NK cells, will be determined in vitro and validated in vivo.
Concluding, the proposed project will enrich our understanding of evasion mechanisms to NK cells and will expedite the breakthrough of next-gen NK cell therapy for head and neck squamous cell carcinomas, with high potential for implementation in additional solid tumors types.
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