RESUMEN
@#Abstract: Objective The method of "molecular docking - molecular dynamics - in vitro pharmacology" was used to screen and optimize small molecule polypeptide compounds that can block PD-1/PD-L1 binding and have high anti-tumor activity. Methods Using the 5-peptide compound database constructed by our team and the three-dimensional structure data of the PD-L1 protein downloaded from the protein database (PDB), the peptide compounds obtained by flexible molecular docking using Molecular Operating Environment software. The molecular dynamics calculation and analysis of the compounds with the highest GWVI/WSA (generalized Born volume integral/weighted surface area) free energy change value (ΔG) were carried out, including the root mean square deviation (RMSD) of the position change of the weight atom and the interaction energy (the sum of Lennard-Jones potential and Coulombic energy). The blocking effect of ligand compounds on PD-1/PD-L1 binding was analyzed by the homogeneous time-resolved fluorescence (HTRF) technique. The co-culture system of Jurkat T lymphocytes and melanoma B16-F10 cells was established to explore the effect of compound ligands on the killing effect of T cells on tumors and the effect on the secretion level of IL-2 in the co-culture supernatant. Results The selected polypeptide compounds were analyzed by molecular dynamics, and the binding of RGGHA to RGGHH and PD-L1 was stable. There are many kinds of interactions between RGGHA and PD-L1，which can compete with PD-1 ligands to bind Asp122, Try123 and Lys124 sites of the PD-L1 protein and block PD-1/PD-L1 signal transduction. HTRF experiments showed that the binding inhibition rate of RGGHA to PD-1 and PD-L1 was 58.38%, and that of RGGHH was 42.73%. In addition, we established a co-culture system of Jurkat T lymphocytes and melanoma B16-F10 cells to explore the immunostimulatory effect and mechanism of peptides. The results show that RGGHA and RGGHH can significantly increase the secretion level of IL-2, improve the killing ability of T cells against tumor cells and activate the tumor immune microenvironment. Conclusions The study found that the polypeptide compounds RGGHA and RGGHH can effectively block the PD-1/PD-L1 interaction and reactivate the anti-cancer immune response, which can be used as lead compounds for new drug development.
RESUMEN
Non-small cell lung cancer (NSCLC) is the most common pathological type of lung cancer. The systemic antitumor therapy of advanced NSCLC has undergone renovations of chemotherapy, targeted therapy and immunotherapy, which results in greatly improved survival for patients with advanced NSCLC. Immune checkpoint inhibitors (ICIs), especially targeting programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1), has changed the treatment paradigm of NSCLC. ICIs have become the standard treatment for advanced NSCLC without epidermal growth factor receptor(EGFR) mutation or anaplastic lymphomakinase(ALK) translocation in the first- or second-line setting, and for locally advanced NSCLC following concurrent radiotherapy and chemotherapy. ICIs are also promising in adjuvant/neoadjuvant therapy. More and more ICIs have been approved domestically for the treatment of NSCLC. Led by the NSCLC expert committee of Chinese Society of Clinical Oncology (CSCO), this consensus was developed and updated based on thoroughly reviewing domestic and foreign literatures, clinical trial data, systematic reviews, experts' discussion and the consensus(2019 version). This consensus will aid domestic clinicians in the treatment of NSCLC with ICIs. .
RESUMEN
@# Advanced gastric cancer is one of cancer types with poor prognosis in East Asia and China. Treatment strategies are especially limited in patients with advanced gastric cancer due to the lack of potent efficacy and serious toxicity. In 2017, immune checkpoint inhibitors targeting programmed cell death protein-1 (PD-1) or programmed death ligand-1 (PD-L1) have been approved by FDA for treating advanced gastric or gastroesophageal junction cancer (GC/GEJC) as a third-line option. However, immune checkpoint inhibitors have not been used in the first or second-line setting for advanced gastric cancer. Presently, many clinical trials are undergoing to determine the efficacy of combined therapy including checkpoint inhibitor plus chemotherapy, dual combinations with two immune checkpoint inhibitors, to enhance anticancer activity of immune checkpoint inhibitors and expand targeted patients. Furthermore, areas for further study include the development and validation of novel biomarkers to predict patients who are most likely to respond to treatment and characterization of outcomes with immune checkpoint inhibitors in different defined disease subgroups.