Chitinase-3-like 1 protein complexes modulate macrophage-mediated immune suppression in glioblastoma

Glioblastoma is a highly malignant and incurable brain tumor characterized by intrinsic and adaptive resistance to immunotherapies. However, how glioma cells induce tumor immunosuppression and escape immunosurveillance remains poorly understood. Here, we find upregulation of cancer-intrinsic chitinase-3-like 1 (CHI3L1) signaling modulating an immunosuppressive microenvironment by reprogramming tumor-associated macrophages (TAMs). Mechanistically, CHI3L1 binding with galectin 3 (Gal3) selectively promotes TAM migration and infiltration with a protumor M2-like, but not an antitumor M1-like, phenotype in vitro and in vivo, governed by a transcriptional program of NF-kappa B/CEBP beta in the CHI3L1/Gal3-PI3K/AKT/mTOR axis. Conversely, galectin 3-binding protein (Gal3BP) negatively regulates this process by competing with Gal3 to bind CHI3L1. Administration of a Gal3BP mimetic peptide in syngeneic glioblastoma mouse models reverses immune suppression and attenuates tumor progression. These results shed light on the role of CHI3L1 protein complexes in immune evasion by glioblastoma and as a potential immunotherapeutic target for this devastating disease.

Automated summary

The CHI3L1 signaling pathway plays a crucial role in modulating the immune suppression microenvironment in glioblastoma by affecting tumor-associated macrophages. Gal3BP competes with Gal3 to bind CHI3L1, thus negatively regulating the immune evasion process. Administering a Gal3BP mimetic peptide in mouse models can reverse immune suppression and slow tumor progression.