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.
Similar content being viewed by others
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
References
Gururangan S, Reap E, Reynolds R, Grant G, Onar-Thomas A, Kocak M, Baxter P, Pollack I, Phillips P, Boyett JM, Fouladi M, Mitchell DA (2016) Immunologic profile of patients with newly-diagnosed medulloblastoma at initial diagnosis and during standard radiation and chemotherapy (PBTC-N11). Neuro Oncol 18(3):iii118
Dolecek TA, Propp JM, Stroup NE, Kruchko C (2012) CBTRUS statistical report: primary brain and central nervous system tumors diagnosed in the United States in 2005–2009. Neuro Oncol 14(Suppl 5):v1–49. doi:10.1093/neuonc/nos218
Gajjar A, Chintagumpala M, Ashley D, Kellie S, Kun LE, Merchant TE, Woo S, Wheeler G, Ahern V, Krasin MJ, Fouladi M, Broniscer A, Krance R, Hale GA, Stewart CF, Dauser R, Sanford RA, Fuller C, Lau C, Boyett JM, Wallace D, Gilbertson RJ (2006) Risk-adapted craniospinal radiotherapy followed by high-dose chemotherapy and stem-cell rescue in children with newly diagnosed medulloblastoma (St Jude Medulloblastoma-96): long-term results from a prospective, multicentre trial. Lancet Oncol 7(10):813–820. doi:10.1016/S1470-2045(06)70867-1
Gururangan S, Krauser J, Watral MA, Driscoll T, Larrier N, Reardon DA, Rich JN, Quinn JA, Vredenburgh JJ, Desjardins A, McLendon RE, Fuchs H, Kurtzberg J, Friedman HS (2008) Efficacy of high-dose chemotherapy or standard salvage therapy in patients with recurrent medulloblastoma. Neuro Oncol 10(5):745–751. doi:10.1215/15228517-2008-044
Jackson CM, Lim M, Drake CG (2014) Immunotherapy for brain cancer: recent progress and future promise. Clin Cancer Res 20(14):3651–3659. doi:10.1158/1078-0432.CCR-13-2057
Poschke I, Mougiakakos D, Kiessling R (2011) Camouflage and sabotage: tumor escape from the immune system. Cancer Immunol Immunother 60(8):1161–1171. doi:10.1007/s00262-011-1012-8
Wainwright DA, Dey M, Chang A, Lesniak MS (2013) Targeting tregs in malignant brain cancer: overcoming IDO. Front Immunol 4:116. doi:10.3389/fimmu.2013.00116
Fecci PE, Mitchell DA, Whitesides JF, Xie W, Friedman AH, Archer GE, Herndon JE 2nd, Bigner DD, Dranoff G, Sampson JH (2006) Increased regulatory T-cell fraction amidst a diminished CD4 compartment explains cellular immune defects in patients with malignant glioma. Cancer Res 66(6):3294–3302. doi:10.1158/0008-5472.CAN-05-3773
Byrne WL, Mills KH, Lederer JA, O’Sullivan GC (2011) Targeting regulatory T cells in cancer. Cancer Res 71(22):6915–6920. doi:10.1158/0008-5472.CAN-11-1156
Hartigan-O’Connor DJ, Poon C, Sinclair E, McCune JM (2007) Human CD4+ regulatory T cells express lower levels of the IL-7 receptor alpha chain (CD127), allowing consistent identification and sorting of live cells. J Immunol Methods 319(1–2):41–52. doi:10.1016/j.jim.2006.10.008
Vignali DA, Collison LW, Workman CJ (2008) How regulatory T cells work. Nat Rev Immunol 8(7):523–532. doi:10.1038/nri2343
Sonabend AM, Ogden AT, Maier LM, Anderson DE, Canoll P, Bruce JN, Anderson RC (2012) Medulloblasoma: challenges for effective immunotherapy. J Neurooncol 108(1):1–10. doi:10.1007/s11060-011-0776-1
Raffaghello L, Nozza P, Morandi F, Camoriano M, Wang X, Garre ML, Cama A, Basso G, Ferrone S, Gambini C, Pistoia V (2007) Expression and functional analysis of human leukocyte antigen class I antigen-processing machinery in medulloblastoma. Cancer Res 67(11):5471–5478. doi:10.1158/0008-5472.CAN-06-4735
Zhou P, Sha H, Zhu J (2010) The role of T-helper 17 (Th17) cells in patients with medulloblastoma. J Int Med Res 38(2):611–619
Dorand RD, Nthale J, Myers JT, Barkauskas DS, Avril S, Chirieleison SM, Pareek TK, Abbott DW, Stearns DS, Letterio JJ, Huang AY, Petrosiute A (2016) Cdk5 disruption attenuates tumor PD-L1 expression and promotes antitumor immunity. Science 353(6297):399–403. doi:10.1126/science.aae0477
Liu D, Song L, Brawley VS, Robison N, Wei J, Gao X, Tian G, Margol A, Ahmed N, Asgharzadeh S, Metelitsa LS (2013) Medulloblastoma expresses CD1d and can be targeted for immunotherapy with NKT cells. Clin Immunol 149(1):55–64. doi:10.1016/j.clim.2013.06.005
Heimberger AB, Kong LY, Abou-Ghazal M, Reina-Ortiz C, Yang DS, Wei J, Qiao W, Schmittling RJ, Archer GE, Sampson JH, Hiraoka N, Priebe W, Fuller GN, Sawaya R (2009) The role of tregs in human glioma patients and their inhibition with a novel STAT-3 inhibitor. Clin Neurosurg 56:98–106
Wei S, Kryczek I, Zou W (2006) Regulatory T-cell compartmentalization and trafficking. Blood 108(2):426–431. doi:10.1182/blood-2006-01-0177
Schneider T, Kimpfler S, Warth A, Schnabel PA, Dienemann H, Schadendorf D, Hoffmann H, Umansky V (2011) Foxp3(+) regulatory T cells and natural killer cells distinctly infiltrate primary tumors and draining lymph nodes in pulmonary adenocarcinoma. J Thorac Oncol 6(3):432–438. doi:10.1097/JTO.0b013e31820b80ca
Ashwell JD, Lu FW, Vacchio MS (2000) Glucocorticoids in T cell development and function*. Annu Rev Immunol 18:309–345. doi:10.1146/annurev.immunol.18.1.309
Mathian A, Jouenne R, Chader D, Cohen-Aubart F, Haroche J, Fadlallah J, Claer L, Musset L, Gorochov G, Amoura Z, Miyara M (2015) Regulatory T cell responses to high-dose methylprednisolone in active systemic lupus erythematosus. PLoS One 10(12):e0143689. doi:10.1371/journal.pone.0143689
Park B, Yee C, Lee KM (2014) The effect of radiation on the immune response to cancers. Int J Mol Sci 15(1):927–943. doi:10.3390/ijms15010927
Medler TR, Cotechini T, Coussens LM (2015) Immune response to cancer therapy: mounting an effective antitumor response and mechanisms of resistance. Trends Cancer 1(1):66–75. doi:10.1016/j.trecan.2015.07.008
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
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.
Electronic supplementary material
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
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
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00262-017-2051-6