Glioma-Derived Factors Induce The Expansion Of Myeloid Derived Suppressor Cells Which Mediate Immune Suppression And Tumor Progression

Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL Glioblastoma multiforme (GBM) is the most common and aggressive primary brain cancer in adults. In spite of improved standard of care (surgery, chemotherapy and radiation) the median survival of GBM patients remains dismal. GBM's therapeutic challenges include its invasiveness, resistance to therapies, and immune suppression. We and others have shown that immune suppressive cells infiltrate the GBM microenvironment, i.e., regulatory T cells and myeloid derived suppressor cells (MDSC). Expansion of MDSCs can be triggered by factors produced by the tumor cells, which interfere with myelopoiesis and inhibit the maturation of myeloid precursor cells. We aimed to study whether intracranial GBMs release factors to the general circulation that induce expansion of MDSCs and their recruitment into the tumor mass. We first explored the ability of GBM cells to release soluble factors that induce MDSC expansion in vitro. When compared to control 3T3 mouse fibroblasts, conditioned media (CM) from GL26 and M7 brain tumor cells expressed high levels of ligands for the receptor for advanced glycation end products (RAGE), i.e., HMGB1, S100A8 and S100A9, which have been shown to play a critical role in the expansion of MDSCs in several cancer models. Tallying with these findings, CM from GL26 and M7 glioma cells induced an increase in the number of MDSC (Gr-1+/Cd11b+) and an inhibition of dendritic cell maturation in bone marrow cultures in vitro. We then implanted intracranial GL26 tumors in syngeneic C57/Bl6 mice and evaluated the infiltration of MDSCs into the brain tumor mass and their expansion in peripheral lymphoid organs during tumor progression, as well as the capacity of GBM cells to release immunossupressive factors in vivo. An increase in circulating RAGE ligands that correlated with tumor progression was observed in the serum of tumor-bearing mice. Expansion of MDSCs was detected in cervical lymph nodes, spleen and blood 2 weeks after tumor implantation. The presence of Gr-1+/Cd11b+ MDSCs was detected within the tumor by flow cytometry at 21 and 35 (moribund) days after implantation. These cells accounted for as much as 30% of total tumor infiltrating immune cells (CD45+). By Confocal microscopy, we found Gr-1+/CD11b+ MDSCs at the tumor border and within the brain tumor mass, as well as GBM cells expressing S1008 and S100A9 and exhibiting cytoplasmic HMGB1. Multiparameter immunophenotypic analysis of bone marrow showed an increase in hematopoietic stem cells and a reduction in common myeloid progenitors, indicating an inhibition of myeloid cells’ differentiation. Our results suggest that GBM-derived factors stimulate peripheral expansion of MDSCs and their recruitment into the tumor mass, eliciting immune-suppression and GBM progression. Thus, manipulation of MDSCs emerges as an attractive therapeutic target for brain cancer. Supported by grants from NIH/NINDS Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3645. doi:10.1158/1538-7445.AM2011-3645