title: Sustained CD4+T cell-driven lymphopenia without a compensatory IL-7/IL-15 response among high-grade glioma patients treated with radiation and temozolomide.
abstract: Prolonged lymphopenia correlating with decreased survival commonly occurs among glioma patients undergoing radiation therapy (RT) and temozolomide (TMZ) treatment. To better understand the pathophysiology of this phenomenon, we prospectively monitored serum cytokine levels and lymphocyte subsets in 15 high-grade glioma patients undergoing combined radiation and TMZ (referred to as RT/TMZ) treatment. Sufficient data for analysis were acquired from 11 of the patients initially enrolled. Lymphocyte phenotyping data were obtained using cytofluorometric analysis and serum cytokine levels were measured using the a multiplex bead-based assays. Total lymphocyte counts (TLCs) were > 1000 cells per μL peripheral blood in 10/11 patients at baseline, but dropped significantly after treatment. Specifically, after RT/TMZ therapy, the TLCs were found to be < 500 cells/μL in 2/11 patients, 500-1000 cells/μL in 7/11 patients, and > 1000 cells/μL in the remaining 2 patients. Among residual mononuclear blood cells, we observed a proportional drop in B and CD4+T cells but not in CD8+T lymphocytes. Natural killer cells remained to near-to-baseline levels and there was a transient and slight (insignificant) increase in regulatory T cells (Tregs). The circulating levels of IL-7 and IL-15 remained low despite marked drops in both the total and CD4+T lymphocyte counts. Thus, patients with malignant glioma undergoing RT/TMZ treatment exhibit a marked decline in TLCs, affecting both CD4+T cells and B lymphocytes, in the absence of a compensatory increase in interleukin-7 levels. The failure to mount an appropriate homeostatic cytokine response may be responsible for the prolonged lymphopenia frequently observed in these patients.
authors.affiliation: Department of Radiation Oncology and Molecular Radiation Sciences; Johns Hopkins University School of Medicine and Sidney Kimmel Comprehensive Cancer Center; Baltimore, MD USA.
authors.forename: Susannah
authors.initials: S
authors.lastname: Ellsworth
authors.affiliation: Department of Radiation Oncology and Molecular Radiation Sciences; Johns Hopkins University School of Medicine and Sidney Kimmel Comprehensive Cancer Center; Baltimore, MD USA.
authors.forename: Ani
authors.initials: A
authors.lastname: Balmanoukian
authors.affiliation: Mayo Clinic Arizona; Phoenix, AZ USA.
authors.forename: Ferdynand
authors.initials: F
authors.lastname: Kos
authors.affiliation: Department of Medical Oncology; Johns Hopkins University School of Medicine and Sidney Kimmel Comprehensive Cancer Center; Baltimore, MD USA.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Nirschl
authors.affiliation: Department of Medical Oncology; Johns Hopkins University School of Medicine and Sidney Kimmel Comprehensive Cancer Center; Baltimore, MD USA.
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Nirschl
authors.affiliation: Department of Medical Oncology; Johns Hopkins University School of Medicine and Sidney Kimmel Comprehensive Cancer Center; Baltimore, MD USA.
authors.forename: Stuart A
authors.initials: SA
authors.lastname: Grossman
authors.affiliation: Department of Medical Oncology; Johns Hopkins University School of Medicine and Sidney Kimmel Comprehensive Cancer Center; Baltimore, MD USA.
authors.forename: Leo
authors.initials: L
authors.lastname: Luznik
authors.affiliation: Department of Medical Oncology; Johns Hopkins University School of Medicine and Sidney Kimmel Comprehensive Cancer Center; Baltimore, MD USA ; James Buchanan Brady Urological Institute; Johns Hopkins University School of Medicine and Sidney Kimmel Comprehensive Cancer Center; Baltimore, MD USA.
authors.forename: Charles G
authors.initials: CG
authors.lastname: Drake
keywords: CD4+ lymphopenia; IL-7; glioblastoma; immunotherapy; lymphocytes; radiation therapy; radiotherapy