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Regulatory T cell subsets in patients with medulloblastoma at diagnosis and during standard irradiation and chemotherapy (PBTC N-11)

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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.

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Abbreviations

CM:

Chiari malformation

GBM:

Glioblastoma multiforme

MBL:

Medulloblastoma

PFT:

Posterior fossa tumors other than medulloblastoma

RT:

Radiotherapy

TH :

Helper T cells

Tregs :

Regulatory T cells

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Authors and Affiliations

  1. The Preston A. Wells Center for Brain Tumor Therapy, McKnight Brain Institute, University of Florida, Room L1-183, Gainesville, FL, 32608, USA

    Sridharan Gururangan & Duane Mitchell

  2. Department of Neurosurgery, University of Florida, Gainesville, FL, USA

    Sridharan Gururangan & Duane Mitchell

  3. Immunotherapy Program, Duke University Medical Center, Durham, NC, USA

    Elizabeth Reap & Robert Schmittling

  4. Department of Neurosurgery, State University of New York, Buffalo, NY, USA

    Renee Reynolds

  5. Department of Neurosurgery, Stanford University, Stanford, CA, USA

    Gerald Grant

  6. Texas Children’s Cancer Center, Houston, TX, USA

    Patricia Baxter

  7. Department of Neurosurgery, Children’s Hospital of Pittsburgh, Pittsburgh, PA, USA

    Ian F. Pollack

  8. Neuro-Oncology Program, Children’s Hospital of Philadelphia, Philadelphia, PA, USA

    Peter Phillips

  9. Neuro-Oncology Program, Cincinnati Children’s Hospital, Cincinnati, OH, USA

    Maryam Fouladi

  10. Operations, Biostatistics, and Data Management Center, The Pediatric Brain Tumor Consortium, Memphis, TN, USA

    Mehmet Kocak, Arzu Onar-Thomas, James Boyett & Maryam Fouladi

  11. University of Tennessee Health Science Center, Memphis, TN, USA

    Mehmet Kocak

Authors
  1. Sridharan Gururangan
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  2. Elizabeth Reap
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  3. Robert Schmittling
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  8. Patricia Baxter
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  9. Ian F. Pollack
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  10. Peter Phillips
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  13. Duane Mitchell
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Corresponding author

Correspondence to Sridharan Gururangan.

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Funding

This work was supported by Pediatric Brain Tumor Consortium Grant U01CA81457, National Center for Research Resources Grant M01RR00188, and the American Lebanese Syrian Associated Charities.

Conflict of interest

The authors declare that they have no conflict of interest.

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Gururangan, S., Reap, E., Schmittling, R. et al. Regulatory T cell subsets in patients with medulloblastoma at diagnosis and during standard irradiation and chemotherapy (PBTC N-11). Cancer Immunol Immunother 66, 1589–1595 (2017). https://doi.org/10.1007/s00262-017-2051-6

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  • DOI: https://doi.org/10.1007/s00262-017-2051-6

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