The study investigates the interaction between the human epidermal growth receptor 2 (HER2) and amygdalin, a compound found in peaches, almonds, and apples. To assess the potential of amygdalin, the interaction between HER2 and amygdalin was explored using molecular docking and molecular dynamics simulations. Binding energies were evaluated for both the crystal and equilibrated HER2 structures. The effects of water on binding were also assessed. Molecular dynamics simulations analyzed structural changes in HER2, including interdomain distances, hydrogen bond fluctuations, dihedral angle shifts, and residue-residue distances at the dimerization arm. The free energy landscape was constructed to evaluate stability. Binding energies of −33.472 ​kJ/mol and −36.651 ± 0.867 ​kJ/mol were observed for the crystal and equilibrated HER2 structures, respectively, with water further enhancing binding to −41.212,4 ​± ​1.272,7 and −53.513 ± 1.452,3 ​kJ/mol. Molecular dynamics simulations revealed significant conformational changes in HER2, including a reduction in interdomain distance, fluctuations in hydrogen bond lengths, and a shift in dihedral angles from 60° to −30°. The residue-residue distance at the dimerization arm decreased, indicating conformational changes upon binding. The free energy landscape showed a deeper and more defined minimum in the bound state, reflecting enhanced stability. These findings highlight amygdalin’s potential as a therapeutic agent targeting HER2.

Regulatory T (T_reg) cells that express a shortened form of FOXP3 can promote cytotoxic T cell-mediated antitumor activity, according to new research involving mice. The study also showed that a synthetic molecule that reprogrammed T_reg cells to express the shorter FOXP3 variant boosted antitumor activity in mouse models and patient-derived tumor organoids. These findings could inform treatments to overcome tumor immunosuppression by T_reg cells that express full-length FOXP3 (FOXP3^FL). While mice only carry a single version of FOXP3^FL, humans express a form of FOXP3 that lacks exon 2 (FOXP3^dE2) and is associated with proinflammatory functions and autoimmune disease. By contrast, T_reg cells that express FOXP3^FL inhibit inflammation, which can dampen antitumor immunity. To investigate how FOXP3^dE2 affects tumor immune responses, Yujing Li and colleagues examined data from patients with triple-negative breast cancer and from a broader cancer genome atlas. They determined that FOXP3^dE2 expression was linked to better patient survival in multiple cancers, while FOXP3^FL expression was associated with poorer outcomes. Furthermore, genetically modified mice with T_reg cells that express FOXP3^dE2 (dE2 T_reg cells) were resistant to tumor growth in several types of cancers. The researchers examined immune cells from the tumor microenvironment and found that dE2 T_reg cells boosted the activation and accumulation of tumor-infiltrating cytotoxic T cells. In addition, dE2 T_reg cells downregulated genes related to immune suppression and T_reg cell stability and upregulated helper T cell features. Li et al. designed a synthetic molecule known as a morpholino, which can bind to FOXP3 mRNA and skip the expression of exon 2 – thus shifting FOXP3^FL to FOXP3^dE2. Morpholino treatment enhanced antitumor immunity in mice and in patient-derived breast cancer and colorectal cancer tumor organoids. “Our study suggests that [morpholino]-mediated FOXP3 isoform shifting is a potentially promising immunotherapeutic approach for cancer treatment,” the authors write.

For reporters interested in trends, a Science Immunology study published in 2022 by some of the same authors examined the role of exon 2 in FOXP3 and T_reg cell function: https://www.science.org/doi/10.1126/sciimmunol.abo5407