Modulation des Tumorstoffwechsels zur Verbesserung der antitumoralen Immunantwort im HNSCC

Objectives: HNSCC has a poor prognosis and checkpoint inhibitors demonstrate limited efficacy. Survival in general and response to immunotherapy depend in particular on intratumoral T cell function, whose activity is impaired by the metabolic microenvironment. Given the observed decrease in glutamine levels in HNSCC and the known negative impact on T cells, effects of pharmacological manipulation of glutamine metabolism were investigated.

Methods: Immune infiltrate, function and ROS levels were analyzed by flow cytometry, Interferon-g (IFNg) was quantified by ELISA. Metabolites were analyzed by mass spectrometry. Pharmacological manipulations were performed ex vivo in fresh tumor fragments and a tumor spheroid immune cell co-culture model.

Results: In both, our patient cohort and a TCGA data set, overall survival was dependent on T cells, which in turn correlated positively with intratumoral glutamine levels. Furthermore, glutamine restriction inhibited T cell function, in particular IFNg levels. Analysis of a TCGA data revealed that patients with high IFNg expression exhibited a superior overall survival rate. Administration of BPTES, a selective glutaminase inhibitor, significantly increased the portion of IFNg expressing T cells in fresh tumor specimens. Furthermore, BPTES had the potential to enhance the efficacy of anti-PD1 therapy. Notably, BPTES had a negligible impact on extracellular glutamine levels. However, it induced ROS and reduced viability of tumor cells but not of T cells.

Conclusion: It can be concluded, that treatment with BPTES impairs the redox status of tumor cells, most likely by interfering with the synthesis of the antioxidant glutathione. Furthermore, BPTES limits tumor cell viability which may stimulate intratumoral T cell activity.

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