# 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.

## Key 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.