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

  • Neurotherapeutics. 2026 Jan;23(1):e00853. doi: 10.1016/j.neurot.2026.e00853.
Eun-Jung Ahn  1 ,  Sung Sun Kim  2 ,  Sm Abdus Salam  1 ,  Eshrat Jahan  1 ,  Sung-Ju Bang  2 ,  Yeong Jin Kim  3 ,  Sue Jee Park  3 ,  Tae-Young Jung  3 ,  Roo Ji Lee  4 ,  Jae-Hyuk Lee  2 ,  Yong Yeon Jeong  5 ,  Min-Hee Yi  6 ,  Joon Haeng Rhee  7 ,  Kyung Keun Kim  8 ,  Kyung-Hwa Lee  9 ,  Kyung-Sub Moon  10
Affiliations
  • 1. Department of Neurosurgery, Chonnam National University Hwasun Hospital and Medical School, Hwasun, South Korea; Department of Pathology, Chonnam National University Hwasun Hospital and Medical School, Hwasun, South Korea.
  • 2. Department of Pathology, Chonnam National University Hwasun Hospital and Medical School, Hwasun, South Korea.
  • 3. Department of Neurosurgery, Chonnam National University Hwasun Hospital and Medical School, Hwasun, South Korea.
  • 4. Department of Rehabilitation, Chonnam National University Hwasun Hospital and Medical School, Hwasun, South Korea.
  • 5. Department of Radiology, Chonnam National University Hwasun Hospital and Medical School, Hwasun, South Korea.
  • 6. Department of Microbiology and Immunology, Chonnam National University Medical School, Hwasun, South Korea; BioMedical Sciences Graduate Program (BMSGP), Chonnam National University, Hwasun, South Korea.
  • 7. Medical Research Center (MRC) for Immunotherapy of Cancer, Chonnam National University Medical School, Hwasun, South Korea.
  • 8. Department of Pharmacology, Chonnam National University Medical School, Hwasun, South Korea.
  • 9. Department of Pathology, Chonnam National University Hwasun Hospital and Medical School, Hwasun, South Korea; BioMedical Sciences Graduate Program (BMSGP), Chonnam National University, Hwasun, South Korea. Electronic address: [email protected].
  • 10. Department of Neurosurgery, Chonnam National University Hwasun Hospital and Medical School, Hwasun, South Korea. Electronic address: [email protected].
PMID: 41688273 DOI: 10.1016/j.neurot.2026.e00853
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.

Keywords
CCL20; Glioblastoma; Immunosuppression; KITENIN; Myeloid-derived suppressor cells; Tumor microenvironment.
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