In Search of Ways to Selectively Inhibit Tumor Infiltrating Regulatory T Cells
Cancers evolve to co-opt aspects of the immune system in order to suppress the immune response to cancerous cells. All tumor tissues make use of a variety of such mechanisms. In principle, sabotaging the immune suppression produced by tumor tissue should be a basis for both novel effective cancer therapies and enhancement of existing immunotherapies for cancer. Here is an example of early stage research in this part of the field, in which researchers identify mechanisms operating in regulatory T cells in tumor tissue. The metabolism of tumor resident regulatory T cells may be sufficiently distinctive to build approaches to treatment that can inhibit regulatory T cell function to harm the tumor without also harming necessary immune function elsewhere in the body.
T cells are central to the body's defense against cancer, with one subset, regulatory T cells (Tregs), playing a unique and often contradictory role in immune response. Unlike conventional T cells that attack tumors, Tregs prevent excessive inflammation and maintain immune tolerance. While this is essential for immune balance, Tregs within tumors, known as tumor-infiltrating Tregs (TIL-Tregs), allow cancer to evade immune attacks by suppressing the activity of effector T cells - the immune cells that actively target and kill tumor cells. Although targeting Tregs to restore anti-tumor immunity is an emerging area in cancer therapy, systemically inhibiting Tregs can cause severe autoimmune reactions.
TIL-Tregs possess unique characteristics compared to Tregs in systemic circulation, maintaining heightened suppressive capabilities within the nutrient-poor conditions of the tumor microenvironment, where effector T cells often falter. While GLUT1 is the primary glucose transporter in conventional T cells, GLUT3 plays a central role in glucose metabolism in TIL-Tregs. Typically associated with neurons, GLUT3 enables TIL-Tregs to efficiently absorb glucose from the tumor microenvironemnt, supporting their suppressive activity.
GLUT3-driven glucose absorption activates a metabolic pathway leading to protein modification with uridine diphosphate N-acetylglucosamine (UDP-GlcNAc), a sugar molecule. This modification process, called O-GlcNAcylation, regulates various proteins, including the transcription factor c-Rel, which is essential for TIL-Tregs' tumor-specific properties. By facilitating O-GlcNAcylation, GLUT3 provides TIL-Tregs with a metabolic advantage that enhances immune suppression within tumors.
This research highlights that TIL-Tregs have unique metabolic adaptations. This paves the way for innovative strategies in cancer immunotherapy that focus on rebalancing immune responses while minimizing adverse effects. Targeting GLUT3 or the O-GlcNAcylation pathway could precisely manipulate Treg activity within tumors, leading to better outcomes in cancer patients.
Targeting TIL-Treg-specific *metabolism* is certainly an interesting variation on the current pharma approaches, which mainly target TIL-Treg-enriched *cell-surface markers* like CCR8 (CHS-114 and LM-108 presentations at ASCO 2024) or ICOS/IL1R1 (Mair et al. Nature 2022, https://www.nature.com/articles/s41586-022-04718-w). In practice these latter approaches seem
How specific truly is GLUT3-driven glucose absorption for TIL-Tregs? This seems like it would be uregulated in *any* conditions of relative nutrient deprivation/limited systemic circulation, not just tumors.