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Ideally, the immune system identifies tumors as threatening elements and deploys immune cells (T cells) to find and kill them. However, many tumor cells have evolved to employ a protein called PD-L1 to blind T cells from carrying out their functions and evade immune defenses. PD-L1 protects tumor cells by activating a "molecular brake" or “checkpoints” known as PD-1 to stop T cells. Remarkably, drugs that block PD-1 or its ligand PD-L1 have proven to release the PD-1 brake from T cells, and demonstrated unprecedented clinical activities in a variety of human cancers. Still, durable response is limited to a small subset of cancer patients. Identification of reliable predictive biomarkers, and targeting other immune checkpoints, either alone or in combination with PD-1 inhibitors, hold the promise of extending the therapy to more tumor types and a larger populations of patients. However, these efforts are slowed down by the incomplete molecular understanding of immune checkpoints.
We are a group of biochemists and cell biologists aiming to dissect the mechanisms of immune checkpoints, using cell-free membrane reconstitution, time-resolved live cell microscopy and cutting-edge cell biology approaches. We recently uncovered two novel aspects of PD-L1/PD-1 signaling. Intracellularly, we showed that the T cell costimulatory receptor CD28 is a primary target of PD-1 associated phosphatases. Extracellularly, we discovered that PD-L1, a key weapon of tumor cells, can be neutralized in cis by PD-1 expressed on the same cells. Now, we will continue to elucidate the PD-1 signaling pathway by identification of novel regulators and targets of PD-1. In addition, we are investigating whether and how additional immune brakes operate in conjunction with PD-1 to “turn off” T cell activity. We will identify the triggering molecules that turn these brakes on, and signal transducers these brakes recruit to suppress the immune response. Our findings could lead to the development of novel biomarkers and drug targets of cancer immunotherapy.
We are a group of biochemists and cell biologists aiming to dissect the mechanisms of immune checkpoints, using cell-free membrane reconstitution, time-resolved live cell microscopy and cutting-edge cell biology approaches. We recently uncovered two novel aspects of PD-L1/PD-1 signaling. Intracellularly, we showed that the T cell costimulatory receptor CD28 is a primary target of PD-1 associated phosphatases. Extracellularly, we discovered that PD-L1, a key weapon of tumor cells, can be neutralized in cis by PD-1 expressed on the same cells. Now, we will continue to elucidate the PD-1 signaling pathway by identification of novel regulators and targets of PD-1. In addition, we are investigating whether and how additional immune brakes operate in conjunction with PD-1 to “turn off” T cell activity. We will identify the triggering molecules that turn these brakes on, and signal transducers these brakes recruit to suppress the immune response. Our findings could lead to the development of novel biomarkers and drug targets of cancer immunotherapy.
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PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICAno. 3 (2024)
Xiaozheng Xu,Preston Dennett,Jibin Zhang, Alice Sherrard,Yunlong Zhao,Takeya Masubuchi,Jack D Bui,Xu Chen,Enfu Hui
The Journal of experimental medicineno. 7 (2023)
bioRxiv : the preprint server for biology (2023)
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Immunityno. 6 (2023): 1187-1203.e12
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Annual review of cell and developmental biologyno. 1 (2023): 391-408
Nature immunologyno. 12 (2023): 2032-2041
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