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A Robotic Microscope System to Examine T Cell Receptor Acuity Against Tumor Neoantigens: A New Tool for Cancer Immunotherapy Research


Sharon Ong L.L. , Zhu H. , Banik D. , Guan Z. , Feng Y. , Reinherz E.L. , Lang M.J. , Asada H.H. . IEEE Robotics and Automation Letters. 2019 ; 4(2). 1760-1767


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During immune surveillance, cytotoxic T lymphocytes (CTL) can selectively identify and destroy tumor cells by recognizing tumor-specific peptides (neoantigens), bound to major histocompatibility complex molecules (pMHC) arrayed on cancer cell surfaces. CTL use the same machinery to destroy virally infected cells displaying pathogen-specific pMHC, while leaving intact healthy cells expressing normal self-pMHC. We present a robotic microscope that allows scientists to conduct highly sensitive and selective T cell-pMHC studies with high throughput. Our system manipulates micro-meter beads coated with particular pMHC, presents them to T cells and generates piconewton-level intermolecular forces required to detect T cell acuity with a neoantigen. Our system integrates optical tweezers, precision nano-micro stages and episcopic/diascopic illumination schemes at two magnifications. We create a coordinate referencing system to locate translucent T cells in 3D, over a large space, based on the characteristic intensity change at each focal plane caused by the cells. Our system performs automated experiments to detect the level of T cell acuity with specific pMHCs, by measuring the downstream cellular responses. High acuity T cells can be selectively recovered for single cell analysis. Our new methodology and tool will have a significant impact on cancer immunotherapy and immunology research.