Related Experiment Video
Updated: Nov 16, 2025
09:40
Co-immunoprecipitation Assay for Studying Functional Interactions Between Receptors and Enzymes
Published on: September 28, 2018
15.5K
Checkpoint inhibition through small molecule-induced internalization of programmed death-ligand 1
Jang-June Park1, Emily P Thi1, Victor H Carpio1
1Arbutus Biopharma Inc, Warminster, PA, USA.
Nature Communications
|February 23, 2021
Summary
A novel small molecule approach inhibits programmed death-ligand 1 (PD-L1) by inducing dimerization and internalization. This method shows promise in reducing colorectal tumors and enhancing immune responses in chronic infections.
Area of Science:
- Immunology
- Molecular Biology
- Oncology
Background:
- Programmed death-ligand 1 (PD-L1) is a key immune checkpoint molecule.
- PD-L1 interaction with programmed death-1 (PD-1) inhibits T cell responses.
- Current therapies targeting PD-L1 involve antibodies disrupting this interaction.
Purpose of the Study:
- To investigate a novel mechanism for inhibiting PD-L1.
- To explore small molecule-induced dimerization and internalization of PD-L1.
- To evaluate the therapeutic potential of this approach in cancer and viral infections.
Main Methods:
- Development of small molecules to induce PD-L1 dimerization and internalization.
- Testing in a humanized mouse model of colorectal cancer.
- Assessment of immune cell responses in patients with chronic hepatitis B.
Main Results:
- Small molecule-induced PD-L1 inhibition significantly reduced tumor size in a colorectal cancer model.
- This approach promoted T cell proliferation.
- Antigen-specific T and B cell responses were elevated in chronic hepatitis B patients treated with the inhibitor.
Conclusions:
- Small molecule-induced PD-L1 internalization offers a new strategy for checkpoint inhibition.
- This mechanism differs from antibody-based therapies.
- The approach demonstrates therapeutic potential for both oncology and chronic viral infections.
Related Concept Videos
01:31The Intrinsic Apoptotic Pathway
7.4K
Internal cellular stress, such as cellular injury or hypoxia, triggers intrinsic apoptosis. The B-cell lymphoma 2 (Bcl-2) family of proteins are the primary regulators of the intrinsic apoptotic pathway. For example, during DNA damage, checkpoint proteins, such as Ataxia Telangiectasia Mutated (ATM protein) and Checkpoints Factor-2 (Chk2) proteins, are activated. These proteins phosphorylate p53 which further activates pro-apoptotic proteins, such as Bax, Bak, PUMA, and Noxa, and inhibits...
7.4K
01:17The Extrinsic Apoptotic Pathway
7.1K
The extrinsic apoptotic pathway is initiated when extracellular death-inducing signals, such as specific cytokines, activate the death receptors expressed on the cell surface. The immune cells involved in this pathway are natural killer cells (NK cells) and cytotoxic T-lymphocytes. NK cells are critical in innate immune response, while cytotoxic T-lymphocytes are associated with adaptive immune response. These cells recognize specific receptors expressed on the altered cells and activate...
7.1K
01:17Phagocytosis of Apoptotic Cells
4.2K
Cells undergoing apoptosis form apoptotic bodies that must be removed immediately to prevent inflammation, autoimmune diseases, and necrosis. Phagocytosis is carried out by professional phagocytes such as macrophages or immature dendritic cells. Non-professional phagocytes such as epithelial cells and fibroblasts also take part in this process; however, they are not as effective as professional phagocytes.
Normal cells contain receptors that prevent them from being recognized...
Normal cells contain receptors that prevent them from being recognized...
4.2K
01:30Apoptosis
12.8K
Apoptosis is a combination of two Greek words, 'apo' and 'ptosis,' meaning separation and falling off, respectively. Hippocrates used this word to describe gangrene, which was caused due to bandaging of fractured bones. Apoptosis was distinguished from necrosis in 1970 when John Kerr reported observations of morphological changes occurring during apoptosis. During one experiment, he observed that the disruption of blood supply to the liver tissue resulted in a size...
12.8K
02:34Inhibition of Cdk Activity
5.3K
The orderly progression of the cell cycle depends on the activation of Cdk protein by binding to its cyclin partner. However, the cell cycle must be restricted when undergoing abnormal changes. Most cancers correlate to the deregulated cell cycle, and since Cdks are a central component of the cell cycle, Cdk inhibitors are extensively studied to develop anticancer agents. For instance, cyclin D associates with several Cdks, such as Cdk 4/6, to form an active complex. The cyclin D-Cdk4/6 complex...
5.3K
01:30Overview of Cell Death
8.4K
Cell death is an essential process where the body gets rid of old or damaged cells. Cell proliferation and death need to be balanced, as an imbalance between the two may lead to cancer or autoimmune diseases.
Cell death was observed in the early 19th century, but there was no experimental evidence to prove it. In 1842, Carl Vogt first discovered cell death in a metamorphic toad; however, it was not termed ‘cell death.’ Scientists discovered different cell death pathways only in the...
Cell death was observed in the early 19th century, but there was no experimental evidence to prove it. In 1842, Carl Vogt first discovered cell death in a metamorphic toad; however, it was not termed ‘cell death.’ Scientists discovered different cell death pathways only in the...
8.4K