Neutrophil Degranulation and Immunosuppression in Patients with GBM: Restoration of Cellular Immune Function by Targeting Arginase I

Abstract

Purpose: The source of glioblastoma (GBM)-associated immunosuppression remains multifactorial. We sought to clarify and therapeutically target myeloid cell-derived peripheral immunosuppression in patients with GBM.Experimental Design: Direct ex vivo T-cell function, serum Arginase I (ArgI) levels, and circulating myeloid lineage populations were compared between patients with GBM and normal donors or patients with other intracranial tumors. Immunofunctional assays were conducted using bulk and sorted cell populations to explore the potential transfer of myeloid cell-mediated immunosuppression and to identify a potential mechanism for these effects. ArgI-mediated immunosuppression was therapeutically targeted in vitro through pharmacologic inhibition or arginine supplementation.Results: We identified a significantly expanded population of circulating, degranulated neutrophils associated with elevated levels of serum ArgI and decreased T-cell CD3z expression within peripheral blood from patients with GBM. Sorted CD11b þ cells from patients with GBM were found to markedly suppress normal donor T-cell function in coculture, and media harvested from mitogen-stimulated GBM peripheral blood mononuclear cell (PBMC) or GBM-associated mixed lymphoid reactions showed ArgI levels that were significantly higher than controls. Critically, T-cell suppression in both settings could be completely reversed through pharmacologic ArgI inhibition or with arginine supplementation. Conclusions: These data indicate that peripheral cellular immunosuppression in patients with GBM is associated with neutrophil degranulation and elevated levels of circulating ArgI, and that T-cell function can be restored in these individuals by targeting ArgI. These data identify a novel pathway of GBM-mediated suppression of cellular immunity and offer a potential therapeutic window for improving antitumor immunity in affected patients. Clin Cancer Res; 17(22); 6992-7002. Ó2011 AACR.

The Role of Inflammation in Kidney Cancer

“…Furthermore, the production of VEGF and bFGF by MDSC is STAT3 dependent since MDSC-mediated angiogenesis can be blocked by STAT3 inhibitors (Kujawski et al 2008). Similar to mouse models, granulocytic (G) MDSC (CD33+HLADR−CD15+CD14−) dominate in the blood of patients with different types of cancer including RCC, GBM, lung, and pancreatic cancer (Rodriguez et al 2009;Zea et al 2005;Peggs et al 2009;Ko et al 2010;Youn et al 2012;Sippel et al 2011). Monocytic (CD33+HLADR−CD15−CD14+) are also present in modest numbers in RCC patients while a population of MDSC not typically seen in mouse models are prevalent in RCC, the linage negative subset (CD33+HLADR−CD15−CD14−) (11,23,25).…”

The Prognostic Value of the Myeloid-Mediated Immunosuppression Marker Arginase-1 in Classic Hodgkin Lymphoma

“…Indeed, we hypothesized that this immunosuppressive activity is mediated by Arg-1. Arg-1 is contained in neutrophils, at the level of cytoplasmic azurophil granules as reported in most cases [24,26,41] but also in gelatinase grains [25]. Arg-1 modifies the metabolism of L-arginine, including the dephosphorylation of cofilin, which is needed for the stability of the immunological synapse [42] and downregulates the CD3ζ chain translation in T cells, contributing to inhibit T cell proliferation [19,22,[29][30][31].…”

The Role of Inflammation in Brain Cancer

“…Arginase converts L-arginine to L-ornithine and urea, thereby depleting L-arginine needed for NO generation. Therefore, neutrophil degranulation within the tumor microenvironment diminishes macrophage-mediated antitumor activity (Sippel et al 2011). Further, depletion of local L-arginine could inhibit the proliferation of T cells, resulting in T-cell dysfunction, which can be reversed by L-arginine supplementation (Sippel et al 2011).…”