NexTGen researchers Dr. Maria Rotiroti and Dr. Robbie Majzner Dr. at Harvard’s Dana-Farber Cancer Institute published a paper in October 2025 in Nature Cancer, entitled “Engineering T cells with a membrane-tethered version of SLP-76 overcomes antigen-low resistance to CAR T cell therapy”
For context, Chimeric Antigen Receptor (CAR) T Cells are immune cells that are designed to express receptors that bind and recognize target antigens on the surface of cancer cells. Once CAR-T Cells recognize their target, they send signals to the rest of their cellular machinery to initiate the killing and elimination of the bound cancer cell. One of the main signaling molecules in this process is called “SLP-76.” SLP-76 is naturally found floating around in the cytosol of the immune cells. The killing signals are much more likely to be successfully sent throughout the cell if SLP-76 happens to be near the CAR complex when it binds its target antigen.
CAR-T Cells require a significant number of targets to be expressed on the surface of cancer cells to allow for enough recognition events to fully induce the killing signal. CAR-T Cell treatment resistance often occurs when cancer cells downregulate the expression of these targets which lowers the potential for recognition events. Our natural immune cells often overcome this as their receptor complexes organize their signaling machinery nearby which minimizes the amount of recognition events needed to successfully send the killing signal. However, engineered CARs are not structured to control the location of these signaling molecules like SLP-76.
To overcome the challenges of low antigen-density CAR-T Cell resistance, the Majzner lab engineered a version of SLP-76 that remains membrane tethered entitled, “MT-SLP-76.” Keeping SLP-76 attached to the membrane increases the likelihood that it will be near the membrane-bound CAR complex. The different locations these complexes can exist in by chance are confined to the 2D surface of the membrane rather than the spacious 3D volume it surrounds. Under these conditions, when the CARs recognize target antigens, they are much more likely to successfully send the signal to kill the cancer cell. This lowers the threshold for antigen-dependent activation and killing. The team engineered immune cells with both a CAR and MT-SLP-76 and found that it restored sensitivity to antigen-low target cells in comparison to plain CAR controls.
Overcoming the obstacle of low antigen-density greatly increases the number of cancers CAR-T cell therapies can be applied to and the number of patients who could receive these life-saving treatments. Additionally, for those that receive CAR-T therapy, it significantly decreases the chance that they develop resistance. Overall, the MT-SLP-76 strategy powerfully increases the potency of CAR-T cells and can help save the lives of cancer patients.
