In-depth immunophenotyping of patients with glioblastoma multiforme: Impact of steroid treatment

Abstract

Despite aggressive treatment regimens based on surgery and radiochemotherapy, the prognosis of patients with grade IV glioblastoma multiforme (GBM) remains extremely poor, calling for alternative options such as immunotherapy. Immunological mechanisms including the Natural Killer Group 2 member D (NKG2D) receptor-ligand system play an important role in tumor immune surveillance and targeting the NKG2D system might be beneficial. However, before considering any kind of immunotherapy, a precise characterization of the immune system is important, particularly in GBM patients where conventional therapies with impact on the immune system are frequently co-administered. Here we performed an in-depth immunophenotyping of GBM patients and age-matched healthy controls and analyzed NKG2D ligand expression on primary GBM cells . We report that GBM patients have a compromised innate immune system irrespective of steroid (dexamethasone) medication. However, dexamethasone drastically reduced the number of immune cells in the blood of GBM patients. Moreover, higher counts of immune cells influenced by dexamethasone like CD45 lymphocytes and non-Vδ2 γδ T cells were associated with better overall survival. Higher levels of NKG2D ligands on primary GBM tumor cells were observed in patients who received radiochemotherapy, pointing towards increased immunogenic potential of GBM cells following standard radiochemotherapy. This study sheds light on how steroids and radiochemotherapy affect immune cell parameters of GBM patients, a pre-requisite for the development of new therapeutic strategies targeting the immune system in these patients.

Effect of Cumulative Dexamethasone Dose during Concomitant Chemoradiation on Lymphopenia in Patients with Newly Diagnosed Glioblastoma

“…A recent study published by Hui et al [ 17 ] calculated the cumulative exposure of dexamethasone during CCRT and showed that increased use of dexamethasone was independently associated with acute severe lymphopenia and OS. Chitadze et al [ 13 ] showed that dexamethasone affects various immune cell parameters not including TLC in GBM patients. Based on our findings and previous reports, female sex seemed to be strongly associated with lymphopenia.…”

“…Several clinical factors have been suggested as contributors to lymphopenia including sex, age, irradiated brain volume, chemotherapy, and the use of dexamethasone [ 11 12 13 14 15 16 17 18 ]. Radiotherapy (RT) was found to be significantly associated with lymphopenia in GBM patients [ 10 11 14 15 16 18 19 ].…”

Radiomic Immunophenotyping of GSEA-Assessed Immunophenotypes of Glioblastoma and Its Implications for Prognosis: A Feasibility Study

“…These features can be utilized to build predictive models for identifying the molecular subtype and immune-related gene expression level within the TME [ 23 , 24 , 25 , 26 ]. In addition, several approaches have been demonstrated as being capable of identifying intratumoral immunophenotypes; these approaches include flow cytometry [ 27 , 28 ], immunohistochemistry [ 29 ], and the transcriptome expression profiling of distinct metagene lists by using gene set enrichment analysis (GSEA) [ 30 , 31 , 32 , 33 , 34 , 35 , 36 ]. These approaches can be used to efficiently estimate the abundances of immune subsets, including CTLs, aDCs, Tregs, and MDSCs.…”

Effects of tumor grade and dexamethasone on myeloid cells in patients with glioma

“…Although the relationship between Dex treatment and circulating myeloid cell frequency or phenotype has been reported, 14 this variable is often overlooked in the development of novel therapeutic targets. Furthermore, though the impact of Dex treatment on immune suppression 15,16 and survival 14 in GBM patients has been studied, it is yet unclear if these effects are systemic or restricted to the tumor microenvironment in patients with low and high grade astrocytomas.…”