PD-L1 blocks new mechanisms against tumors to reveal that dendrite cells play a key role.

Source: Dr. Wei Xu, author of the science Translational Medicine paper and vice president of biology and translational medicine at Synda Biochemicals, believes the new findings could have positive implications for screening patients in the clinic and guiding combination medications in the future.
since the first PD-1 drug was introduced in 2014, PD-1/PD-L1 pathway inhibitors have revolutionized clinical anti-tumor therapy.
way to kill tumors by blocking PD-1 or PD-L1 through antibodies to release the T-cell "brake" and re-active the T-cells is a completely T-cell-centric way of working.
there was a theory that a patient's tumor should first express the PD-L1 protein, with PD-1/PD-L1 inhibitor seupret.
facts do show similar effects -- the higher the expression of PD-L1 in patients, the better the clinical outcome.
But it was later found that some PD-L1-negative patients also had good clinical outcomes, while only a small number of PD-L1-positive patients benefited from PD-1/PD-L1 inhibitors.
data suggest that PD-1/PD-L1 inhibitors have other undeded immune mechanisms.
In this new study, Dr. Wei Xu and others uncovered the answer to this question in a new study in which the expression of PD-L1 was much higher than that of B7.1 in destocyte cells in cancer patients.
studies indicate that PD-L1 has two ligands, PD-1 and B7.1, which is an important costimulating ligand on myelin cells, especially dendritic cells.
dendrite cell expression B7.1 binds to the Cd28 receptor of T cells, which is a key step in The Functional Activity of T Cells.
blocking the PD-L1/B7.1 interaction on dendritic cells enhances CD28 signals on T cells (Source: Science Translational Medicine) Studies show that dendritic cells in patients' tumors express both PD-L1 and B7.1, while PD-L1 is at least 20 times higher than b7.1.
These two molecules bind to the surface of dendrite cells, and a large number of PD-L1s "bury" B7.1 in the cell membrane, leaving B7.1 with no chance to bind to CD28 on T cells, meaning that antigen-presenting cells lose the ability to activate T-cells.
When patients use PD-L1 antibodies, a portion of the antibodies bind to PD-L1 on dendritic cells, blocking the binding and encapsulation of PD-L1 and B7.1, allowing B7.1 to be released and re-binding to T CD28 on the cells, forming super immune synapses (Immune Synapse, refers to the site of cell-to-cell binding in the process of cell recognition and binding with antigens, a structure that promotes The transduction, activation, and effective play of cell effects of T-cell signals).
dendrite cells treated with anti-PD-1 can induce T-cell initiation (Source: Science Translational Medicine) Researchers also simulated the pathoglyptical proliferation of dendrite cells after PD-L1 antibody binding.
, more importantly, they found a positive correlation between genes that expressed thyroid cells in pre-treatment tumor tissue in patients with kidney and non-small cell lung cancer and clinical efficacy (total survival rate).
in cancer patients, dendritic cell characteristics are associated with improved survival benefits for PD-L1 antibody atezolizumab (Source: Science Translational Medicine, Science Translational Medicine, Science Translational Medicine, AndeleS. Pujanandez, in an opinion piece entitled "Checkpoint Musical", said that PD-L1/B7.1 interaction seditular binding on dendritic cell membranes has implications for the treatment of PD-L1.
Another important implication of this new study is that while there is no evidence that PD-L1 is superior to PD-1 in the entire immune activation pathway due to its additional function in activating desysyblast cells, one thought is whether combined blocking PD-1 and PD-L1 will lead to clinical synergies."
based on this thinking, Synda Bio initiated the world's first dual-specific antibody (IBI318) that targets both PD-1 and PD-L1.
IBI318 has three functions: 1) blocking PD-1/PD-L1 and resurrecting T-cell killing activity; The function of tumor cells;3) As suggested in this new paper, by blocking the PD-L1/B7.1 interaction on dendritic cells, b7.1 is released to stimulate T cells, promote the tumor antigen presentation, and then induce tumor antigen-specific T-cell differentiation and maturation.
, the project is currently in China and the United States in phase I clinical trials.
related papers: maud Mayoux et al. Dendritic cells dictate responses to PD-L1 blockade cancer immunotherapy. Science Translational Medicine (2020).