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- Title
Chitinase-3-like 1 protein complexes modulate macrophage-mediated immune suppression in glioblastoma.
- Authors
Apeng Chen; Yinan Jiang; Zhengwei Li; Lingxiang Wu; Santiago, Ulises; Han Zou; Chunhui Cai; Sharma, Vaibhav; Yongchang Guan; McCarl, Lauren H.; Jie Ma; Wu, Yijen L.; Michel, Joshua; Yi Shi; Konnikova, Liza; Amankulor, Nduka M.; Zinn, Pascal O.; Kohanbash, Gary; Agnihotri, Sameer; Songjian Lu
- 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.
- Subjects
IMMUNOSUPPRESSION; BRAIN tumors; GLIOBLASTOMA multiforme; LABORATORY mice; CARRIER proteins; IMMUNE complexes
- Publication
Journal of Clinical Investigation, 2021, Vol 131, Issue 16, p1
- ISSN
0021-9738
- Publication type
journal article
- DOI
10.1172/JCI147552