Introduction: Cancer-induced immunosuppression, both local and systemic forms, may play an important role in tumor progression. Currently, this pathology poses a significant challenge to the viability of immunotherapy as a treatment for brain malignancy. Investigations into immune regulatory molecules, in particular B7-H4 (B7X, B7S1), have revealed some extent of their immunomodulatory capacity, especially in inciting immunosuppression, and have linked increasing levels of B7-H4 with poor clinical prognosis in various cancers.
Methods: Mfs /microglia was isolatied from peripheral blood and tissues by microbeads. Cell migration was done by using Transwell assay. Flow cytometry was done for detecting surface B7-H4, CD11b or CD133 expression. Subcutaneous glioma model was done using U87 cells injected into the right flank of NOD/SCID mice.
Results: We first illustrate an association of B7-H4 with the notorious biological features of intracranial gliomas. Next, we show that CD133+ glioma cells induce normal human macrophages (Mfs) to express B7-H4 via IL-6 and IL-10 in tumor environment. Interestingly, we observed that glioma infiltrating macrophages/microglia (GIMs) also stimulate CD133+ cells to induce B7-H4 expression and auto-regulation via IL-6. Given the historical emphasis on a pivotal role of human CD133+ glioma stem-like cells (GSCs) in tumor progression and recurrence, along with the designation of Mfs/microglia as the principal tumor-in?ltrating immune cells in glioblastoma, we sought to determine if B7-H4 localization to GIMs is perhaps a required featured for sustaining the tumor microenvironment. We go on to elaborate on the effects of B7-H4 expression, depicting that CD133+ cells contribute to immunopathology through suppressive B7-H4+ Mfs in vitro and in vivo.
Conclusions: Our data supports the utility of B7-H4 as a novel biomarker of glioma and presents previously unrecognized evidence that increased B7-H4 expression due to suppressive cross talk between CD133+ cells and GIMs hinders dendritic cells (DCs)-based immunotherapy.
Patient Care: We demonstrated that B7-H4 may be clinically useful as a biomarker for human gliomas because its tumor concentration given its clinical implications correlated negatively with prognostic function and positively with malignancy grading. Moreover, we demonstrate that the increase of B7-H4 in GIMs, mediated by GSCs and GIMs themselves, constitutes a previously unrecognized and relevant target for improving therapeutic outcomes of DCs-based active immunotherapy in patients with malignant gliomas.
Learning Objectives: Investigate te role of immune regulatory molecules B7-H4 between CD133+ glioma cells and macrophages/microglia.