Abstract
The plasma-protein histidine-rich glycoprotein (HRG) is implicated in phenotypic switching of tumor-associated macrophages, regulating cytokine production and phagocytotic activity, thereby promoting vessel normalization and antitumor immune responses. To assess the therapeutic effect of HRG gene delivery on CNS tumors, we used adenovirus-encoded HRG to treat mouse intracranial GL261 glioma. Delivery of Ad5-HRG to the tumor site resulted in a significant reduction in glioma growth, associated with increased vessel perfusion and increased CD45+ leukocyte and CD8+ T-cell accumulation in the tumor. Antibody-mediated neutralization of colony-stimulating factor-1 suppressed the effects of HRG on CD45+ and CD8+ infiltration. Using a novel protein interaction-decoding technology, TRICEPS-based ligand receptor capture (LRC), we identified Stanniocalcin-2 (STC2) as an interacting partner of HRG on the surface of inflammatory cells in vitro and colocalization of HRG and STC2 in gliomas. HRG reduced the suppressive effects of STC2 on monocyte CD14+ differentiation and STC2-regulated immune response pathways. In consequence, Ad5-HRG-treated gliomas displayed decreased numbers of IL35+ Treg cells, providing a mechanistic rationale for the reduction in GL261 growth in response to Ad5-HRG delivery. We conclude that HRG suppresses glioma growth by modulating tumor inflammation through monocyte infiltration and differentiation. Moreover, HRG acts to balance the regulatory effects of its partner, STC2, on inflammation and innate and/or acquired immunity. HRG gene delivery therefore offers a potential therapeutic strategy to control antitumor immunity. Mol Cancer Ther; 17(9); 1961-72. ©2018 AACR.
Highlights
Histidine-rich glycoprotein (HRG) is a cation- and heparinbinding, 75-kDa plasma glycoprotein produced by liver hepatocytes, present in blood at a concentration of 150 mg/mL (2 mmol/L; ref. 1)
The effect of histidine-rich glycoprotein (HRG) in tumor growth and spread has been studied by delivering purified recombinant protein, HRG-derived peptides, or by expressing HRG in tumor cells [9, 11, 13, 36]
This indicated that HRG may be therapeutically beneficial for tumors in the central nervous system (CNS)
Summary
Histidine-rich glycoprotein (HRG) is a cation- and heparinbinding, 75-kDa plasma glycoprotein produced by liver hepatocytes, present in blood at a concentration of 150 mg/mL (2 mmol/L; ref. 1). Histidine-rich glycoprotein (HRG) is a cation- and heparinbinding, 75-kDa plasma glycoprotein produced by liver hepatocytes, present in blood at a concentration of 150 mg/mL HRG comprises two N-terminal cystatin domains, and a Cterminal His/Pro-rich repeat region [2]. The plasma levels of HRG in healthy adults are stable, the protein is continuously taken up and turned over by leukocytes [3]. HRG binds heparan sulfate with high affinity [4]. It binds to several components of the complement system [5] and to immunoglobulins [6], Note: Supplementary data for this article are available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
