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

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Abstract

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 NFκB/CEBPβ 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.

Authors

Apeng Chen, Yinan Jiang, Zhengwei Li, Lingxiang Wu, Ulises Santiago, Han Zou, Chunhui Cai, Vaibhav Sharma, Yongchang Guan, Lauren H. McCarl, Jie Ma, Yijen L. Wu, Joshua Michel, Yi Shi, Liza Konnikova, Nduka M. Amankulor, Pascal O. Zinn, Gary Kohanbash, Sameer Agnihotri, Songjian Lu, Xinghua Lu, Dandan Sun, George K. Gittes, Qianghu Wang, Xiangwei Xiao, Dean Yimlamai, Ian F. Pollack, Carlos J. Camacho, Baoli Hu