Sridharan Gururangan1,2, Elizabeth Reap3, Robert Schmittling3, Mehmet Kocak4,5, Renee Reynolds6, Gerald Grant7, Arzu Onar-Thomas4, Patricia Baxter8, Ian F Pollack9, Peter Phillips10, James Boyett4, Maryam Fouladi11,4, Duane Mitchell12,13. 1. The Preston A. Wells Center for Brain Tumor Therapy, McKnight Brain Institute, University of Florida, Room L1-183, Gainesville, FL, 32608, USA. gururangan@ufl.edu. 2. Department of Neurosurgery, University of Florida, Gainesville, FL, USA. gururangan@ufl.edu. 3. Immunotherapy Program, Duke University Medical Center, Durham, NC, USA. 4. Operations, Biostatistics, and Data Management Center, The Pediatric Brain Tumor Consortium, Memphis, TN, USA. 5. University of Tennessee Health Science Center, Memphis, TN, USA. 6. Department of Neurosurgery, State University of New York, Buffalo, NY, USA. 7. Department of Neurosurgery, Stanford University, Stanford, CA, USA. 8. Texas Children's Cancer Center, Houston, TX, USA. 9. Department of Neurosurgery, Children's Hospital of Pittsburgh, Pittsburgh, PA, USA. 10. Neuro-Oncology Program, Children's Hospital of Philadelphia, Philadelphia, PA, USA. 11. Neuro-Oncology Program, Cincinnati Children's Hospital, Cincinnati, OH, USA. 12. The Preston A. Wells Center for Brain Tumor Therapy, McKnight Brain Institute, University of Florida, Room L1-183, Gainesville, FL, 32608, USA. 13. Department of Neurosurgery, University of Florida, Gainesville, FL, USA.
Abstract
BACKGROUND: We evaluated circulating levels of immunosuppressive regulatory T cells (Tregs) and other lymphocyte subsets in patients with newly diagnosed medulloblastoma (MBL) undergoing surgery compared to a control cohort of patients undergo craniectomy for correction of Chiari malformation (CM) and further determined the impact of standard irradiation and chemotherapy on this cell population. METHODS: Eligibility criteria for this biologic study included age 4-21 years, patients with CM undergoing craniectomy (as non-malignant surgical controls) and receiving dexamethasone for prevention of post-operative nausea, and those with newly diagnosed posterior fossa tumors (PFT) undergoing surgical resection and receiving dexamethasone as an anti-edema measure. Patients with confirmed MBL were also followed for longitudinal blood collection and analysis during radiotherapy and chemotherapy. RESULTS: A total of 54 subjects were enrolled on the study [22-CM, 18-MBL, and 14-PFT]. Absolute number and percentage Tregs (defined as CD4+CD25+FoxP3+CD127low/-) at baseline were decreased in MBL and PFT compared to CM [p = 0.0016 and 0.001, respectively). Patients with MBL and PFT had significantly reduced overall CD4+ T cell count (p = 0.0014 and 0.0054, respectively) compared to those with CM. Radiation and chemotherapy treatment in patients with MBL reduced overall lymphocyte counts; however, within the CD4+ T cell compartment, Tregs increased during treatment but gradually declined post therapy. CONCLUSIONS: Our results demonstrate that patients with MBL and PFT exhibit overall reduced CD4+ T cell counts at diagnosis but not an elevated proportion of Tregs. Standard treatment exacerbates lymphopenia in those with MBL while enriching for immunosuppressive Tregs over time.
BACKGROUND: We evaluated circulating levels of immunosuppressive regulatory T cells (Tregs) and other lymphocyte subsets in patients with newly diagnosed medulloblastoma (MBL) undergoing surgery compared to a control cohort of patients undergo craniectomy for correction of Chiari malformation (CM) and further determined the impact of standard irradiation and chemotherapy on this cell population. METHODS: Eligibility criteria for this biologic study included age 4-21 years, patients with CM undergoing craniectomy (as non-malignant surgical controls) and receiving dexamethasone for prevention of post-operative nausea, and those with newly diagnosed posterior fossa tumors (PFT) undergoing surgical resection and receiving dexamethasone as an anti-edema measure. Patients with confirmed MBL were also followed for longitudinal blood collection and analysis during radiotherapy and chemotherapy. RESULTS: A total of 54 subjects were enrolled on the study [22-CM, 18-MBL, and 14-PFT]. Absolute number and percentage Tregs (defined as CD4+CD25+FoxP3+CD127low/-) at baseline were decreased in MBL and PFT compared to CM [p = 0.0016 and 0.001, respectively). Patients with MBL and PFT had significantly reduced overall CD4+ T cell count (p = 0.0014 and 0.0054, respectively) compared to those with CM. Radiation and chemotherapy treatment in patients with MBL reduced overall lymphocyte counts; however, within the CD4+ T cell compartment, Tregs increased during treatment but gradually declined post therapy. CONCLUSIONS: Our results demonstrate that patients with MBL and PFT exhibit overall reduced CD4+ T cell counts at diagnosis but not an elevated proportion of Tregs. Standard treatment exacerbates lymphopenia in those with MBL while enriching for immunosuppressive Tregs over time.
Entities:
Keywords:
CD4; Immunotherapy; Medulloblastoma; Posterior fossa tumors; Regulatory T cells
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