Immune modulation effects of concomitant temozolomide and radiation therapy on peripheral blood mononuclear cells in patients with glioblastoma multiforme

Abstract

Concomitant radiation therapy (RT) and temozolomide (TMZ) therapy after surgery is the standard treatment for glioblastoma multiforme (GBM). Radiation and chemotherapy can affect the immune system with implications on subsequent immune therapy. Therefore, we examined the phenotype and function of peripheral blood mononuclear cells in 25 patients with GBM prior to and 4 weeks after treatment with RT-TMZ using multicolor flow cytometry, as well as in vitro CD4(+) regulatory T cell (T(reg)) suppressor and dendritic cell maturation assays. RT-TMZ induced significant lymphopenia, with a decrease in total CD4(+) T cells, but did not significantly change monocyte counts. The proportion of functional T(reg) cells increased after treatment, whereas their absolute numbers remained stable. There was also a measurable decrease in the proportion of CD8(+)CD56(+) and absolute number of CD3(-)CD56(+) effector cells. Posttherapy monocytes retained the ability to mature into dendritic cells. Treatment with RT-TMZ is associated with changes in regulatory and effector peripheral blood mononuclear cells that tilt the balance towards an immune suppressive state. This shift can affect the outcome of immune therapy following RT-TMZ treatment and should be considered in the design of future combination therapy regimens.

NK Cells in Central Nervous System Disorders

“…Patients with glioma are known to have impaired immune function, parallel to an increase of anti-inflammatory molecules in plasma (20). Fadul et al (21) observed decreased absolute numbers of NK cells in PBMCs isolated from glioblastoma multiforme (GBM) patients who were treated with combined radiation therapy and temozolomide. Furthermore, NK cell frequency and their cytotoxic activity (NKCA) were shown to be affected in the blood of brain tumor patients as well as in animal glioma models (22,23).…”

Immunological effects of chemotherapy and radiotherapy against brain tumors

“…Fadul et al assessed the effect of radiotherapy and TMZ on peripheral blood monocytes and lymphocytes in patients with glioblastoma after four weeks of treatment. The authors observed a treatment-related shift towards a suppressive immunophenotype characterized by enrichment of Tregs and decreased NK and CD8 + T cells (41). Another prospective study with a similar design confirmed this treatment-related lymphopenia.…”

The role of regulatory T cells and microglia in glioblastoma-associated immunosuppression

“…Multiple studies have suggested that lymphopenia, which is commonly seen following standard radiation and temozolamide therapy in patients with GBM, results in a proportional increase in circulating Tregs during the ''trough'' period [29,30]. During a trial of EGFRvIII vaccination in patients with GBM, Sampson et al noted that functional measures of in vivo vaccine response were somewhat paradoxically improved in the setting of increasing lymphopenia [30].…”