Novel Determinants of PD-L1 Protein Trafficking and Stability in Lung Adenocarcinoma Cells
Abstract
Expression of programmed cell death ligand 1 (PD-L1) by lung adenocarcinoma cells prevents them from being recognized and eliminated by the patient’s immune system. Immunotherapy designed to block the interaction between PD-L1 and its binding partner, PD-1, which is expressed by immune cells, has unprecedented therapeutic benefit in lung adenocarcinoma patients. However, a considerable fraction of patients lacks initial response or stop responding to anti-PD-L1 immune checkpoint therapies. This fact underscores the need to better understand the basic molecular mechanisms that regulate PD-L1-mediated immune evasion in lung adenocarcinoma. Exposure on the surface of lung adenocarcinoma cells is necessary for preventing cancer cell recognition by immune cells. Prior to cell surface localization, PD-L1 needs to be modified with sugars. Our pilot experiments have shown that a small molecule prevents PD-L1 sugar modification and surface expression in lung adenocarcinoma cells. Using this compound, we plan to dissect the molecular mechanisms that facilitate the modification of PD-L1 with sugars and its expression on the surface of lung cancer cells. We will also investigate the effects of this compound on the recognition of lung adenocarcinoma cell by immune cells. This knowledge will help improve responses to current anti-PD-L1 immunotherapies and facilitate the design of novel anti-PD-L1 strategies such as those based on the use of this compound and its derivatives. The proposed research is highly relevant to the LCRP Concept Award area of emphasis, “understand the molecular mechanisms of initiation and progression to clinically significant lung cancer.” Lung cancer cause tremendous morbidity and mortality among Veterans, their families, and the American public, being the number one cause of deaths by cancer. Our proposal seeks to increase our knowledge on the biology of lung cancer with the goal to improve immunotherapeutic treatments to extend the life of lung cancer patients.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010463
Entities
People
- Begona Diaz
Organizations
- Harbor–UCLA Medical Center
- United States Army