KITENIN-CCL20 axis is a potential therapeutic target for modulating immunosuppressive tumor microenvironment in glioblastoma

TL;DR

This study identifies a protein pathway that contributes to immune suppression in brain tumors, suggesting a new target for treatment.

Contribution

The study reveals the KITENIN-CCL20 axis as a novel therapeutic target for modulating immunosuppression in glioblastoma.

Findings

KITENIN overexpression increases CCL20 levels and suppresses cytotoxic T cells in glioblastoma.

CCL20 neutralization reduces tumor growth and myeloid-derived suppressor cells in mice.

KITENIN and CCL20 co-directional expression correlates with poor survival in GBM patients.

Abstract

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-Ly6Chigh 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.

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