Gliomas Promote Immunosuppression through Induction of B7-H1 Expression in Tumor-Associated Macrophages

Abstract

Purpose Gliomas are known to induce local and systemic immunosuppression, inhibiting T cell-mediated cytotoxic responses to tumor growth. Tumor-associated macrophages are a significant component of the immune infiltrate in gliomas and may express immunosuppressive surface ligands, such as B7-H1. Experimental Design Tumor and peripheral blood samples from patients with glioblastoma (GBM) were analyzed by flow cytometry to evaluate the expression of B7-H1 in circulating and tumor-infiltrating macrophages. Human monocytes from healthy patients were stimulated with conditioned media from glioma cells to evaluate B7-H1 expression. Production of IL-10 by stimulated monocytes was measured by ELISA, and stimulation with IL-10 alone was evaluated for the ability to induce B7-H1 expression. The effect of inhibiting IL-10 and its receptor on glioma-induced B7-H1 expression in monocytes was evaluated. Results Circulating monocytes in patients with GBM had significantly increased expression of B7-H1 compared to healthy control patients. Tumor-associated macrophages from matched GBM tissue had even greater B7-H1 expression. Treatment of normal monocytes with glioma conditioned media could significantly increase B7-H1 expression. Stimulation of monocytes with conditioned media resulted in substantial production of IL-10 and upregulation of the IL-10 receptor. Stimulation of monocytes with IL-10 alone could significantly increase B7-H1 expression, sufficient to induce T cell apoptosis when co-cultured with stimulated monocytes. Inhibition of IL-10 and the IL-10 receptor could knock down the effect of glioma media on B7-H1 by greater than 50%. Conclusions Gliomas can upregulate B7-H1 expression in circulating monocytes and tumor-infiltrative macrophages through modulation of autocrine/paracrine IL-10 signaling, resulting in an immunosuppressive phenotype.

IL-12 Regulates B7-H1 Expression in Ovarian Cancer-associated Macrophages by Effects on NF-κB Signalling

“…These results were different from our previous study, in which THP-1-derived macrophages without IL-12 treatment cocultured with SKOV3 showed upregulation of B7-H1 expression as same as monocyte-derived macrophages (Xiong et al, 2014). However, other studies have provided data suggesting that IL-10 could induce B7-H1 expression, whereas neutralizing antibody against IL-10 significantly blocked B7-H1 expression (Kuang et al, 2009;Bloch et al, 2013). So we speculate that IL-12 down-regulated B7-H1 expression in THP-1-derived macrophages cocultured with SKOV3 main through inhibiting the expressions of IL-10, since IFN-γ was absent.…”

Immunosuppressive Myeloid Cells’ Blockade in the Glioma Microenvironment Enhances the Efficacy of Immune-Stimulatory Gene Therapy

“…18,19 Gliomas have been shown to employ a variety of mechanisms to suppress the immune system, such as downregulation of MHC class I molecules, production of transforming growth factor-b (TGF-b), vascular endothelial growth factor (VEGF), prostaglandin E2, and IL-10, expression of ligands of checkpoint receptors, such as PD-1, and accumulation of immunosuppressive cells, such as myeloidderived suppressor cells (MDSCs), regulatory T cells (Tregs), and tumor-associated macrophages (TAMs). [23][24][25][26][27][28][29][30] It has been previously shown in human samples and experimental GBM models that MDSCs are powerful inhibitors of anti-tumor immune responses. 30,31 Through a variety of mechanisms that inhibit T cell activation and expansion, including the production of arginase and inducible nitric oxide synthase (iNOS), reactive oxygen species and/or reactive nitrogen species (ROS and/or RNS), release of IL-10, expansion of regulatory T cells (Tregs), and inhibition of T cell migration, MDSCs have been shown to promote immunosuppression and tumor progression.…”

The Role of Astrocytes in Tumor Growth and Progression

“…Targeting and blocking PD-L1 or PD-1 with antibody therapies has been an effective treatment for several cancers [185,186]. It has been shown that GBM tumors highly express PD-L1, in addition to infiltrating microglia [187,188]. Normal astrocytes have also been found to highly express PD-L1, however astrocyte expression of PD-L1 in a tumor setting has not yet been investigated [189].…”