Abstract 5372: KITENIN leads immunosuppression in the glioblastoma microenvironment via CCL20

Abstract

Abstract Background: Glioblastoma (GBM) is characterized by an immunosuppressive tumor microenvironment (TME), limiting the effectiveness of existing treatments. The author investigated the role of KAI1 COOH-terminal interacting tetraspanin (KITENIN) in mediating this immunosuppression, focusing on its effect on cytokine secretion and tumor-infiltrating lymphocyte (TIL) profiles in the TME. Materials and Methods: Using cytokine array and Luminex multiplex assays, the author evaluated cytokine secretion in KITENIN-modulated GL261 cells. The author further isolated TILs from an orthotopic mouse model implanted with these cells and induced in vitro differentiation of myeloid cells. The effect of neutralizing antibody for target cytokine, was assessed in vivo, and clinical relevance was investigated using GBM patient data from our cohort and TCGA. Results: 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 CD4+Foxp3+ regulatory T cells (Tregs) were observed to be higher in brain tumor implanted with KIT-HA GL261. Furthermore, KIT-HA GL261 conditioned medium expanded CD45+CD11b+Gr1-Ly6c+ 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. Conclusion: These findings underscore the KITENIN-CCL20 axis as a promising target for alleviating the immunosuppressive TME in GBM, potentially unlocking new avenues for GBM immunotherapy. Citation Format: Eun-Jeong Ahn, Nah Ihm Kim, Sung Sun Kim, Jae-Hyuk Lee, Joon Haeng Rhee, Kyung-Keun Kim, Hangun Kim, Kyung-Hwa Lee, Kyung-Sub Moon. KITENIN leads immunosuppression in the glioblastoma microenvironment via CCL20 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5372.