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Gururangan et al. Neuroimmunol Neuroinflammation 2018;5:45 I http://dx.doi.org/10.20517/2347-8659.2018.44 Page 5 of 15
Neoantigen load and immune landscape of common pediatric brain tumors
In the last few years, advances in next generation sequencing in pediatric brain tumors has yielded a wealth
of knowledge on the molecular landscape of various tumors including low grade gliomas, medulloblastomas,
malignant gliomas (including diffuse pontine gliomas), ependymomas, and atypical teratoid rhabdoid
[29]
tumors . However, the overarching theme from these studies is that while actionable mutations do
exist in all these tumors, the mutational load is significantly much lower than carcinogen-induced adult
malignancies (non-small lung cancer or melanomas) except in the case of mismatch repair deficiency (MMR)
induced malignant gliomas in children [30,31] . Unrepaired DNA damage in these tumors due to the somatic
or germline mutations of MSH1, MSH2, MSH6, or PMS-2, POLE, or POLD1 genes results in accumulation
of an inordinate number of additional non-synonymous mutations resulting in a high neoantigen load and
increased immunogenicity against these tumors due to lack of induction of central tolerance [30-32] .
Recent studies of the immune landscape of pediatric brain tumors demonstrates a tumor micro-environment
that is variable across different tumor types. In an immune assay of 91 gliomas [glioblastoma multiforme
(GBM) 68 and pilocytic astrocytoma 23] by immunohistochemistry (IHC), the CD8+ lymphocytes, CD56+
NK cells, and CD68+ macrophages were significantly higher in grade IV infiltrative glioma as compared
[33]
to non-infiltrative grade I pilocytic astrocytoma . Similarly, in a prospective randomized therapeutic trial
TM
in pediatric high grade gliomas using a backbone of bevacizumab (Avastin . Genentech corporation, San
TM
Francisco, CA) in patients receiving radiotherapy plus temozolomide (Temodar , Merck Co., Kenilworth,
NJ), CD8+ infiltration (both perivascular and intratumoral) was highest in both MMR deficient malignant
gliomas (four cases with somatic POLE or POLD1 mutations; median mutation count of 4848, range 2197-
[32]
5332) and anaplastic pleomorphic xanthoastrocytomas (with BRAF alterations) . In this same study,
RNA-sequencing data in a subset of samples revealed CD8 T cell effector/T cell signature that correlated
with CD8+ T cell infiltration by IHC. This signature was particularly prominent in tumors with mitogen
activated protein kinase pathway activation (including BRAF v600e, NF-1, and FGFR1 mutations and
NTRK2 translocation). However, the histone mutant mid-line tumors (carry H3F3A mutations) had notable
[32]
absence of immune infiltrates . An IHC analysis of the antigen processing machinery (APM) in astrocytic
tumors (4 each of grade I-IV gliomas) revealed down regulation of the APM proteins LMP-2, TAP1, and β2
microglobulin without change in the surface human leukocyte antigen (HLA)-class I protein expression .
[34]
[35]
In 26 medulloblastoma samples, Vermeulen et al. found CD3+ T cell intratumoral and/or perivascular
in distribution. The number of CD3+ tumor infiltrating lymphocytes (TILs) was at a median of 23.5 per 2
mm3 of tumor tissue. The phenotype was predominantly CD8+ T cells (52%) followed by CD4+ (35%) and
CD4+CD25+ Fox P3 (2.5%) regulatory T cells. The number of TILs was not different between histologic or
molecular subtypes of this tumor. There was also low CTL activation evidenced by only a small percentage
of T-cells expressing granzyme B (3.9%; maximum 35%). In addition, decreased cell activation was attributed
to a complete lack of expression of MHC class I on tumor cells (HLA-A and B) and CD1 d. Down regulation
of MHC class I complex in medulloblastoma has similarly been reported in other studies [36,37] . One study
of 10 primary medulloblastoma samples observed that while down regulation of class I molecules and
associated proteins of APM machinery was found in these samples, HLA class I restricted tumor antigen
specific CTLs that were generated by stimulation with DCs containing tumor mRNA, were able to effectively
lyse medulloblastoma cell lines in a HLA-restricted manner, suggesting that down regulation or absence of
[37]
MHC class I molecules or APM did not impact on tumor recognition by CTLs . In addition, tumor cells
expressed serpins (granzyme inhibitors) including serpin B1 and serpin B4 as additional means of immune
evasion. The immune environment in ependymomas has been shown to determine patient prognosis
between the two recently described molecular groups (Group A and B) [38,39] ; in the unfavorable group A
tumors, the gene expression pattern has more cell infiltration and immune gene signatures that indicate
an immunosuppressive environment; in group B tumors there exists more of an immune stimulating
response possibly predicting for a better prognosis in patients with these tumors both at initial diagnosis and
following recurrence . Furthermore, recurrent tumors from group A had higher expression of genes related
[40]
to inflammation and immunoregulatory function and recurrent group B tumors had antiviral and adaptive