IGFBP2 promotes immunosuppression associated with its mesenchymal induction and FcγRIIB phosphorylation in glioblastoma.

Yunmian Liu,Sonya Wei Song,Chunyan Song,Jing Zhang,Faping Shen,Jung Weon Lee

doi:10.1371/journal.pone.0222999

Abstract

Immunotherapy shows a promise for treating glioblastoma (GBM), the most malignant and immunosuppressive glioma. The mesenchymal phenotype of cancer cells was frequently reported to be associated with their induction of immunosuppression within the cancer microenvironment. Overexpressed insulin-like growth factor binding protein 2 (IGFBP2) promotes GBM cell migration and invasion, and contributes to glioma progression and cancer recurrence and poor survival in GBM. However, whether IGFBP2 can induce immunosuppression in GBM was not reported yet. Thus, the study applied a syngeneic mouse GBM model, human GBM samples, and cancer-immune cell co-culture experiments to investigate the effect of IGFBP2 on GBM exposed immune cells and its association with the mesenchymal induction. We found that IGFBP2 promoted the mesenchymal feature of GBM cells. The inhibition of IGFBP2 relieved immunosuppression by increasing CD8+ T and CD19+ B cells and decreasing CD163+ M2 macrophages. Further, the IGFBP2-promoted immunosuppression was associated with its induction of the mesenchymal feature of GBM cells and the inhibitory phosphorylated FcγRIIB of GBM exposed immune cells. Blocking IGFBP2 suppressed tumor growth and improved survival of tumor bearing mice in the mouse GBM model. These findings support the notion that targeting the IGFBP2 may present an effective immunotherapeutic strategy for mesenchymal GBMs.

Highlights

Glioblastomas (GBMs) are the most common and deadly primary brain tumors and have inevitable local recurrence, contributing to the most brain tumor-related mortality in adults
As the mesenchymal traits are tightly related to immunosuppression in cancer, we examined the effect of insulin-like growth factor binding protein 2 (IGFBP2) on immune cells exposed to GBM cells by using the GL261-spleen lymphocytes (SPCs) co-culture experiments and the mouse GBM model
Previous studies showed that amino terminus-derived epitopes of IGFBP2 elicited T cell immunity by production of IFN-γ through T helper 1 (Th1) cells, but which is abrogated by its carboxyl terminus-derived epitopes through inducing Th2-producing IL-10[30,31,32]

Summary

Introduction

Glioblastomas (GBMs) are the most common and deadly primary brain tumors and have inevitable local recurrence, contributing to the most brain tumor-related mortality in adults. The standard therapy for the disease includes surgery, radiotherapy, chemotherapy, and chemoradiotherapy. Despite the improvements in these therapies, the median survival of the patients with GBMs is well under 2 years and few long-term survivors exist[1].

Methods

Results

Conclusion