Improving the Ability of Immune Cells to Distinguish Tumor Cells from Healthy Tissue
BioE Assistant Professor Yinnian Feng and an international team of researchers have published a breakthrough study in Cell titled “Tuning the sensitivity of mechanosensory receptors through histidine scanning.” The study addresses a central challenge in T-cell therapy: while T cells use receptors (TCR) to recognize tumor antigens, many tumors evade the immune system by mutating those antigens. While engineering TCRs with enhanced sensitivity can help, it often creates a specificity issue where T cells can no longer distinguish between tumor cells and healthy “self” moieties, resulting in dangerous off-target toxicities.
The research team found that for a natural T cell operating in the body, mechanical force is the “missing factor” that allows it to achieve extraordinary precision. T cell activation correlates with the formation of catch bonds—non-covalent interactions that strengthen under mechanical force (similar to a Chinese finger trap).
To capitalize on this, the study introduces a method called histidine scanning to engineer TCRs with enhanced catch bond formation. By systematically substituting residues in the TCR with histidine, the team discovered productive “hotspot” residues that consistently emerged across more than ten human and mouse TCRs. The engineered T cells demonstrated superior tumor recognition in multiple animal models—including melanoma, hematologic malignancies, colorectal cancer, and osteosarcoma—while maintaining antigen specificity and showing no off-target toxicity.
The Feng Lab at Northeastern contributed the single-molecule optical trapping experiments that provided direct biophysical evidence for catch bond enhancement by histidine mutations. Using “optical tweezers,” the lab measured how histidine variants form longer-lived catch bonds under physiologic force levels. This mechanistic link between molecular engineering and mechanobiology outcomes aligns with the Feng Lab’s core mission to use microfluidics and biophysics to decode how immune cells feel mechanical forces and turn that knowledge into therapy.