Regulatory T cell subsets in patients with medulloblastoma at diagnosis and during standard irradiation and chemotherapy (PBTC N-11)
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.
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.
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.
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.
KeywordsMedulloblastoma Immunotherapy Regulatory T cells CD4 Posterior fossa tumors
Posterior fossa tumors other than medulloblastoma
Helper T cells
Regulatory T cells
Compliance with ethical standards
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.
- 1.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):iii118PubMedCentralGoogle Scholar
- 3.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 CrossRefPubMedGoogle Scholar
- 4.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 CrossRefPubMedPubMedCentralGoogle Scholar
- 8.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 CrossRefPubMedGoogle Scholar
- 10.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 CrossRefPubMedGoogle Scholar
- 13.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 CrossRefPubMedGoogle Scholar
- 15.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 CrossRefPubMedPubMedCentralGoogle Scholar
- 17.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 56:98–106PubMedGoogle Scholar
- 19.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 CrossRefPubMedGoogle Scholar
- 21.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 CrossRefPubMedPubMedCentralGoogle Scholar