CELL INTELLIGENCE · 肿瘤细胞治疗研究

Glioblastoma (GBM) is characterized by an immunosuppressive tumor microenvironment (TME), limiting the effectiveness of existing treatments.

We investigated the role of KAI1 COOH-terminal interacting tetraspanin (KITENIN), a metastasis-promoting protein, in mediating this immunosuppression, focusing on its effect on cytokine secretion and tumor-infiltrating lymphocyte (TIL) profiles in the TME. Employing cytokine array and Luminex multiplex assays, we found increased level of CC chemokine ligand 20 (CCL20) within KITENIN-overexpressed (KIT-HA) GL261 cell supernatants.

Immunohistochemical analyses using GBM samples confirmed that both KITENIN and CCL20 expressions co-directionally increased, and this was associated with decreased survival by TCGA analysis. Myeloid-derived suppressor cells (MDSCs), macrophages, and regulatory T cells were increased in brain tumors implanted with KIT-HA GL261. In contrast, functional cytotoxic T cells were decreased in the KIT-HA group.

Furthermore, compared with control conditioned medium, KIT-HA GL261 conditioned medium expanded CD45 + CD11b + Ly6G - Ly6C high monocytic MDSCs (M-MDSCs), an effect that was abrogated by CCL20 downregulation. In vivo neutralization of CCL20 resulted in reduced tumor volume, prolonged survival, and decreased M-MDSCs, thus affirming the role of CCL20 in mediating immunosuppression.

Our findings underscore the KITENIN-CCL20 axis as a promising target for alleviating the immunosuppressive TME in GBM, potentially unlocking new avenues for GBM immunotherapy.