Stärkung der T-Zell-Funktion unter Glutaminrestriktion durch Expression der Glutaminsynthetase

Objective: T cells are highly dependent on glutamine to sustain metabolic activity and function. Own data reveal that Head and neck squamous cell carcinomas (HNSCC) are frequently characterized by low glutamine levels, which have been associated with a diminished T cell response, potentially affecting also the efficacy of adoptive T cell transfer therapies. We hypothesize, that expression of glutamine synthetase (GS), catalyzing the de-novo synthesis of glutamine from glutamate, could mitigate the effects of glutamine restriction on T cells.

Methods: GS was overexpressed in human CD4+ T cells by retroviral transduction. GS-expressing cells were analysed for cellular metabolism, proliferation and cytokine production under glutamine-restricted conditions. Furthermore, the anti-tumour activity of GS-expressing T cells was evaluated in co-cultures with HNSCC 3D tumour spheroids.

Results: Retroviral transduction resulted in strong and robust GS expression in human T cells. GS expression restored T cell respiratory and glycolytic activity, in particular in the presence of glutamate. Furthermore, GS expression rescued proliferation and elevated Interferon-g secretion under glutamine deprivation. Of significant importance, upon co-cultivation with HNSCC spheroids GS-expressing T cells showed increased effector functions in the presence of low glutamine concentrations.

Conclusion: The results of our study indicate that GS expression represents a promising strategy to enhance anti-tumour T cell effector functions in low glutamine environments, suggesting that metabolic engineering of T cells could be a potential strategy in cell therapy approaches.

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