Glucose deprivation and identification of TXNIP as an immunometabolic modulator of T cell activation in cancer.

BACKGROUND

The ability of immune cells to rapidly respond to pathogens or malignant cells is tightly linked to metabolic pathways. In cancer, the tumor microenvironment (TME) represents a complex system with a strong metabolism stress, in part due to glucose shortage, which limits proper T cell activation, differentiation and functions preventing anti-tumor immunity.

METHODS

In this study, we evaluated T cell immune reactivity in glucose-restricted mixed lymphocyte reaction (MLR), using a comprehensive profiling of soluble factors, multiparametric flow cytometry and single cell RNA sequencing (scRNA-seq).

RESULTS

We determined that glucose restriction potentiates anti-PD-1 immune responses and identified thioredoxin-interacting protein (TXNIP), a negative regulator of glucose uptake, as a potential immunometabolic modulator of T cell activation. We confirmed TXNIP downregulation in tumor infiltrating T cells in cancer patients. We next investigated the implication of TXNIP in modulating immune effector functions in primary human T cells and showed that TXNIP depletion increased IFN-γ secretion and tumor cell killing.

CONCLUSIONS

TXNIP is at the interface between immunometabolism and T cell activation and could represent a potential target for immuno-oncology treatments.