Molecular Mechanism of γδ1T-Derived IL-17D Promoting Malignant Biological Behavior of Breast Cancer through Activation of CD93/Cbl/Rho Molecular Axis

Abstract

Objective: In women, breast cancer (BC) is the most common malignant tumor, accounting for 7–10% of the incidence of various malignant tumor throughout the body. The purpose of this study was to investigate the role of γδ1T cells-derived interleukin (IL)-17D in BC and its molecular mechanism. Methods: The γδ1T cells were isolated from human BC tissues using magnetic beads and identified by flow cytometry. MDA-MB-231 cells or cells co-cultured with γδ1T cells were injected subcutaneously into nude mice at a dose of 5 × 10⁶ cells/mouse to construct an animal model of BC. Enzyme-Linked Immunosorbent Assay (ELISA), Western blot, cell cloning, and scratch test were used to detect malignant biological behavior of BC cells. Observation of mammary carcinoma pathology in nude mice was conducted using hematoxylin-eosin (HE) staining. Results: In in vitro cell experiments, co-immunoprecipitation demonstrated the presence of binding relationships between IL-17D and CD93 as well as between Src and Casitas B-spectrum lymphoma (Cbl). γδ1T-derived IL-17D targeted activation of the breast cancer CD93 receptor and promoted Src-mediated phosphorylation of Cbl, which in turn induced Rho family activation, ultimately promoting MDA-MB-231 cell proliferation, migration, invasion, and epithelial–mesenchymal transition (EMT), enhancing the malignant biological behavior of BC cells. In in vivo experiments, γδ1T promoted an increase in tumor size, volume, and weight, as well as T-cell infiltration and ki-67 expression in cancerous tissues in nude mice, promoting EMT, and thus, malignant progression of BC. Conclusions: γδ1T-derived IL-17D promotes BC progression through activation of the CD93/Cbl/Rho molecular axis.