Scientists at Pohang University of Science and Technology (POSTECH) and ShanghaiTech University have achieved a breakthrough in cancer immunotherapy research. Led by Professors Sin-Hyeog Im and Dipayan Rudra, the research team, with Dr. Amit Sharma as the first author, has identified GLUT3, a glucose transporter, as essential to the suppressive function of regulatory T cells (Tregs) in the tumor microenvironment (TME). This discovery provides new insights into immune cell metabolism within tumors and highlights GLUT3 and glucose-mediated protein modifications as promising targets for cancer immunotherapy. Their findings were published in the latest issue of Cellular & Molecular Immunology.
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. This challenge has focused researchers on understanding Tregs’ tumor-specific mechanisms to selectively target Tregs within tumors without impacting the immune system as a whole.
Professor Im explains that TIL-Tregs possess unique characteristics compared to Tregs in systemic circulation, maintaining heightened suppressive capabilities within the nutrient-poor conditions of the TME, where effector T cells often falter. This resilience inspired the team to investigate glucose uptake and utilization in TIL-Tregs, leading them to identify the critical role of GLUT3. 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 TME, supporting their suppressive activity. The team found that high expression of GLUT3 (encoded by the gene SLC2A3 ) and Treg infiltration correlate with poorer outcomes in various cancers, while GLUT1 (SLC2A1) does not have the same impact. In a genetically engineered mouse model, the researchers demonstrated that selectively removing GLUT3 in Tregs significantly reduced tumor growth without affecting the Tregs' normal functions, opening a new therapeutic pathway.
The team further explored how glucose uptake sustains TIL-Tregs’ suppressive power. Through RNA sequencing, metabolomics, and isotope-tracing studies, they discovered that 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.
Interestingly, the researchers found that increasing protein O-GlcNAcylation in GLUT3 knock-out Tregs—using an enzyme inhibitor called Thiamet-G—led to greater tumor growth, further confirming the link between GLUT3-driven O-GlcNAcylation and TIL-Treg function. Analysis of TIL-Tregs from human colon cancer patients validated this relationship, showing elevated levels of c-Rel O-GlcNAcylation in the tumor environment.
This research highlights that TIL-Tregs have unique metabolic adaptations, enabling them to thrive in the TME and effectively suppress immune responses. By pinpointing GLUT3’s critical role in shaping TIL-Treg functionality, the study lays the groundwork for developing targeted therapies that could boost anti-tumor immune responses without compromising overall Treg function, thus minimizing the risk of autoimmune side effects. Dr. Amit Sharma, the study’s lead author and a postdoctoral researcher in Professor Im’s lab, emphasized the significance of GLUT3 in defining TIL-Tregs’ functionality, noting, “It will be fascinating to explore how different modes of glucose transport influence the metabolic fate of glucose within cells,” underscoring the potential of GLUT3-targeted therapies to strengthen anti-tumor immunity.
In conclusion, the discovery points to a promising direction for future cancer therapies by identifying metabolic vulnerabilities in TIL-Tregs, paving 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.
Cellular and Molecular Immunology
Glut3 promotes cellular O-GlcNAcylation as a distinctive tumor-supportive feature in Treg cells
28-Oct-2024