Induction of Tumor-Associated Phenotype in Normal Fibroblasts by Glioma Cell Apoptotic Bodies

Tumor-associated fibroblasts (TAFs) are a key cellular component of solid tumors, including gliomas. They support the growth of malignant cells, stimulate their invasion and metastasis, induce chemoresistance, and suppress the antitumor immune response. TAFs are formed from resident stromal cells under the influence of tumor cell secretome, including growth factors, chemokines, and extracellular vesicles. Communication between malignant cells and TAFs occurs through direct cell-cell contacts and exchange of secreted molecules and membrane vesicles. In this work, apoptotic bodies (apoBDs) were obtained from two types of glioma cells (T98g cell line and Gbl25 cells isolated from a glioblastoma biopsy) and characterized for surface markers. The surface of tumor apoBDs contained glioblastoma tumor-associated markers, such as GD2 ganglioside and A2B5 antigen. Glioma apoBDs contained lower levels of "don't eat me" molecules and higher levels of "eat me" molecules compared to the original intact glioma cells. On one hand, glioma apoBDs reduced the viability of normal dermal fibroblasts in a dose-dependent manner; on the other hand, they initiated their transformation into the inflammatory subtype of TAFs (iTAFs). iTAFs obtained in this way demonstrated upregulated transcription of genes encoding cytokines, chemokines, and growth factors (IL17A, IL18, IL33, IFN-γ, CCL3, CCL5, CXCL1, CXCL5, CXCL10, CXCL12, TGFB1, and TNF) responsible for maintaining both tumorigenesis itself and the ability of fibroblasts to support it. It was found that glioma apoBDs were able to transfer tumor-associated markers (GD2 ganglioside and A2B5 antigen) to normal fibroblasts. The assessment of the effects of anti-GD2 antibody-drug conjugates (ADCs) on TAFs suggests the possibility of development of targeted drugs effective not only against tumor cells but also against tumor stroma.