Leukocyte Differentiation by Histidine-Rich Glycoprotein/Stanniocalcin-2 Complex Regulates Murine Glioma Growth through Modulation of Antitumor Immunity

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 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. .

Prognostic Value of an Immune-Related Gene Signature in Oral Squamous Cell Carcinoma

“…APOD has been reported to exhibit tumor suppressive activity in some types of tumors (24). OLR1, STC2, and DKK1 correlate with tumor evolution and immunosuppressive effects (25)(26)(27)(28)(29). TNFRSF19, TNFRSF4, DEFB1, CTLA4, and CTSG were identified as protective genes.…”

Integrated Profiles Analysis Identified a Coding-Non-Coding Signature for Predicting Lymph Node Metastasis and Prognosis in Cervical Cancer

“…For example, decreased expression of HRG was observed in advanced lung cancer and is associated with the disease stage (Winiarska et al, 2019). Another study has reported that HRG suppresses glioma growth by modulating antitumor immunity through regulating leukocyte differentiation (Roche et al, 2018).…”

Histidine-Rich Glycoprotein Inhibits High-Mobility Group Box-1-Mediated Pathways in Vascular Endothelial Cells through CLEC-1A

“…Stanniocalcin-2 (STC2) was also reported as an interacting partner of HRG on the surface of inflammatory cells in vitro. The colocalization of HRG and STC2 in gliomas may play a role for suppressing glioma growth by modulating tumor inflammation through monocyte infiltration and differentiation (Roche et al, 2018). However, whether the interaction of HRG with STC2 may influence the HRG-CLEC-1A-mediated signaling need to be clarified in the future.…”