Pharmacological Targeting of GLUT1 to Control Autoreactive T Cell Responses

Abstract

An increasing body of evidence indicates that bio-energetic metabolism of T cells can be manipulated to control T cell responses. This potentially finds a field of application in the control of the T cell responses in autoimmune diseases, including in type 1 diabetes (T1D). Of the possible metabolic targets, Glut1 gained considerable interest because of its pivotal role in glucose uptake to fuel glycolysis in activated T cells, and the recent development of a novel class of small molecules that act as selective inhibitor of Glut1. We believe we can foresee a possible application of pharmacological Glut1 blockade approach to control autoreactive T cells that destroy insulin producing beta cells. However, Glut1 is expressed in a broad range of cells in the body and off-target and side effect are possible complications. Moreover, the duration of the treatment and the age of patients are critical aspects that need to be addressed to reduce toxicity. In this paper, we will review recent literature to determine whether it is possible to design a pharmacological Glut1 blocking strategy and how to apply this to autoimmunity in T1D.

Manipulation of Glucose Availability to Boost Cancer Immunotherapies

“…Several inhibitors of glycolysis have been developed over the years, including 2-deoxiglucose. More recently, a novel class of small molecules displaying high selectivity against glucose transporter 1 (Glut1) and with good pharmacokinetic and pharmacodynamic characteristics have been produced [ 7 ]. The pharmacological blockade of Glut1 is therefore a promising strategy to boost both a long-lasting immune response and reduce tumor growth.…”

Development and validation of a CpG island methylator phenotype‐related prognostic signature for cholangiocarcinoma

“…A novel Th17 antibody‐modified liposome polycation‐DNA complex (LPD) containing encapsulated siRNA against TSPAN1 (Th17‐LPDT) was reported to inhibit the development of gastric cancer by decreasing the polarization of CD4 + T cells (Lu et al, 2020). SLC2A1 is a major glucose transporter in mammalian cells and was also demonstrated to be closely associated with the immune response, including the activation and differentiation of T cells, as well as the glucose metabolism of macrophages and inflammation (Di Dedda et al, 2019; Freemerman et al, 2019). In addition, previous research identified that PPARGC1A and GPRC5A play a role in immunity and inflammation (Jing et al, 2020; Xu et al, 2019).…”

Application of a simple unstructured kinetic and cost of goods models to support T‐cell therapy manufacture

“…T-cells have a cytoplasmic pool of Glut1 that are transported to the cell surface following activation and is linked closely to a peak in glucose uptake between 48 to 72 h post activation 29,30 . If Glut1 is blocked, the capacity of proliferating naïve T-cells to transform into TSCM is severely compromised.…”

“…However, as a new therapeutic class based on a relatively unexplored bioprocess input material, primary T-cells manufacturing technology is particularly immature 3 . The knowledge of process control and its impacts on product quality, such as population distributions and yield, are significantly understudied relative to more established biopharmaceuticals 5 . This lack of knowledge restricts the opportunity for operational optimisation that might drive down costs and/or create more consistent product 6 .…”