Reinvigoration of exhausted T-cell by targeted activation of lipid scramblase, TMEM16F
Inventors: Florian Winau, Yu Hu
Invention Types: Therapeutics
Research Areas: Oncology/Hematology, Infectious Disease
Keywords: For More Information Contact: Ives, Catherine L.
T cell function is central to the adaptive immune response and is required to clear infectious pathogens and cancer. Antigen binding by T cell receptor initiates a signaling cascade necessary for T cell activation. Persistent T cell signaling, occurring in chronic infections and cancer, lead to the development of T cell exhaustion, a dysfunctional T cell state. Exhausted T Cells have compromised effector functions making them unable to clear infections and cancer.
Reinvigoration of T cells by inhibiting checkpoint receptors, such as CTLA4 or PD-1, are actively used in the clinic for cancer treatment. Although immune checkpoint blockades have a substantial clinical benefit, only half of the patients respond and many present immune-related adverse events and possibly relapse 2-3 years after treatment. Therefore, there is an unmet need for novel therapeutic approaches to reduce adverse events while increasing the efficacy of the treatment.
Dr. Winau and his team identified a lipid scramblase -TMEM16F- as a key regulator for protecting T cells, especially cytotoxic T lymphocytes (CTLs), from severe exhaustion during chronic viral infection. The team has shown that mice lacking TMEM16F completely fail to clear virus infection due to compromised T cell responses. These mice also showed a significant increase in expression of exhaustion markers, including PD-1, on CD8 cells. Dr. Winau proposes that targeted activation of TMEM16F may halt the development of T cell exhaustion and further promote virus clearance in chronic viral infections, such as acquired immune deficiency syndrome (AIDS) and chronic hepatitis. While the same strategy alone may also function to clear cancer, combining targeted activation of TMEM16F alongside immune checkpoint therapies may serve as a synergistic therapeutic strategy.
• Prevention and reinvigoration of T cell exhaustion to enhance the immune system’s ability to fight chronic infections, like HBV, HIV and cancer.
• Complimentary cancer treatment to be combined with immune checkpoint therapies.
Novel approach for T cell reinvigoration through targeted activation of lipid scrambles TMEM16F.
Sponsored research and collaboration
Key Publications: Hu Y, Kim JH, He K, Wan Q, Kim J, Flach M, Kirchhausen T, Vortkamp A, Winau F. Scramblase TMEM16F terminates T cell receptor signaling to restrict T cell exhaustion. JEM. 2016 Nov 14;213(12):2759-2772. Epub 2016 Oct 24.
IPStatus: Pat. Pend.